EA043309B1 - BISPECIFIC ANTIBODY CONSTRUCTS ENGAGING T CELLS - Google Patents

Description

State of the art

Bispecific molecules, such as BiTE® (bispecific T cell-engaging molecule) antibody constructs, are recombinant protein constructs consisting of two flexibly linked antibody-derived binding domains. One binding domain of BiTE® antibody constructs is specific for a selected tumor-associated surface antigen on target cells; the second binding domain is specific for the CD3 subunit of the T cell receptor complex on T cells. Due to their specific structure, BiTE® antibody constructs are uniquely suited to temporarily link T cells to target cells and, at the same time, to effectively activate the characteristic cytolytic potential of T cells against target cells. An important additional development of the first generation of BiTE® antibody constructs (see WO 99/54440 and WO 2005/040220), which entered clinical practice as AMG 103 and AMG 110, was the provision of bispecific antibody constructs that bind to a context-independent epitope at the N-terminus CD3ε chains (WO 2008/119567). BiTE® antibody constructs binding to this selected epitope not only demonstrate cross-species specificity for the human CD3ε chain and Callithrix jacchus, Saguinus oedipus or Saimiri sciureus, but also, by recognizing this particular epitope instead of previously described epitopes of CD3 binding components in bispecific molecules, T-cell-engaging antibodies do not activate T cells in a nonspecific manner to the same extent as was observed for the previous generation of T-cell-engaging antibodies. This decrease in T cell activation was associated with less or reduced T cell redistribution in patients, the latter being identified as a risk for adverse events.

The antibody constructs described in WO 2008/119567 are likely to be rapidly cleared from the body; therefore, although they are capable of quickly reaching most parts of the body, are quickly produced and are easy to handle, their in vivo applications may be limited by their short-lived presence in vivo. Due to the short in vivo half-life of this small single-chain molecule, long-term administration by continuous intravenous infusion was used to achieve therapeutic effect. However, such prolonged intravenous infusions are considered inconvenient for patients and, therefore, in the case of more convenient alternative treatment approaches, preclude the selection of a compound that has demonstrated greater effectiveness in treating the disease in question. Accordingly, there is a need in the art for bispecific therapeutics that maintain similar therapeutic efficacy, that are in a format that allows for ease of manufacture, and that have favorable pharmacokinetic properties, including a longer half-life.

Increased half-life is generally beneficial in in vivo applications of immunoglobulins, particularly antibodies, and specifically small-sized antibody fragments. Approaches described in the art to achieve this effect involve fusing a small bispecific antibody construct with larger proteins that preferably do not interfere with the therapeutic effect of the BiTE® antibody construct. Examples of such additional developments of bispecific molecules engaging T cells include bispecific Fc molecules, for example, described in US 2014/0302037, US 2014/0308285, WO 2014/144722, WO 2014/151910 and WO 2015/048272. An alternative strategy is the use of HSA fused to a bispecific molecule or a simple fusion of human albumin binding peptides (see, for example, WO 2013/128027, WO 2014/140358).

Brief description of the invention

All half-life extending formats (HLE formats) of bispecific T cell-engaging molecules described in the art include the hetero-Fc (also referred to as hetFc or heterodimeric Fc, hFc) format and fusions of human serum albumin (also referred to as HSA or hALB), have individual disadvantages such as nonspecific T-cell activation, complement activation, instability, or a pharmacokinetic profile that is not consistent with the required extension of the half-life of the molecules. It is therefore an object of the present invention to provide a half-life extending format of bispecific T cell engaging molecules that eliminates at least one, and certainly preferably more than one, of these individual disadvantages observed with prior art molecules. Accordingly, this invention provides bispecific antibody constructs with a specific Fc modality characterized by containing a first domain that binds to a target cell surface antigen, a second domain that binds to an extracellular epitope of the human and/or Macaca CD3ε chain, and a third domain that is a specific modality of Fc. In addition, the invention provides a polynucleotide encoding an antibody construct, a vector containing this polynucleotide, host cells expressing the construct, and a pharmaceutical composition containing the above.

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Description of the figures

Fig. 1: in fig. 1a is a diagram of one embodiment of an antibody design according to the invention. In fig. 1b shows the heterodimeric Fc antibody design, and FIG. 1c depicts an X-body design as described in the art. These charged pairs are introduced to enhance heterodimerization. In fig. 1d depicts the product of a fusion of an antibody construct with human serum albumin (HSA or hALB).

Fig. 2: Evaluation of target-independent T cell activation by HLE BiTE® antibody constructs with mesothelin (MS). 2(a) antibody design according to the invention in a 48 hour activation assay with human PBMCs (3x); serial dilutions of HLE BiTE® (starting from 20 nM; 1:5, 7x+control); without or with FcR blocking [10 mg/ml huIgG (Kiovog, Baxter)]; FACS measurement of CD69 and CD25 expression [not shown] on CD4+, CD8+ T cells. 2(b) hetero-Fc antibody construct in 48 h activation assay by human PBMCs and PBMCs lacking CD14+/CD33+ cells (3x); serial dilutions of HLE BiTE® (starting from 20 nM; 1:5, 7x+control); FACS measurement of CD69 and CD25 expression [not shown] on CD4+, CD8+ T cells.

Fig. 3: Evaluation of target-independent T cell activation by HLE BiTE® antibody constructs. 3(a) construction of a CDH19 antibody according to the invention in a 48 hour activation assay with human PBMCs (3x); serial dilutions of HLE BiTE® (starting from 20 nM; 1:5, 7x+control); without or with FcR blocking [10 mg/ml huIgG (Kiovog, Baxter)]; FACS measurement of CD69 and CD25 expression [not shown] on CD4+, CD8+ T cells. 3(b) hetero-Fc antibody construct CDH19 in 48 h activation assay by human PBMCs and PBMCs lacking CD14+/CD33+ cells (3x); serial dilutions of HLE BiTE® (starting from 20 nM; 1:5, 7x+control); FACS measurement of CD69 and CD25 expression [not shown] on CD4+, CD8+ T cells. 3(c) CDH19 X-body construct in 48 h activation assay by human PBMCs and PBMCs lacking CD14+/CD33+ cells (3x); serial dilutions of HLE BiTE® (starting from 20 nM; 1:5, 7x+control); FACS measurement of CD69 and CD25 expression [not shown] on CD4+, CD8+ T cells; 3(d)-3(aa), isolated PBMCs from three different healthy human donors were cultured for 48 hours with increasing concentrations of bispecific HLE antibody constructs specific for different target antigens. Expression of the activation marker CD69 on CD4+ and CD8+ T cells was determined by flow cytometry analysis using a PE-Cy7-conjugated mab specific for CD69.

Fig. 4: C1q complement binding by BiTE® Fc fusion antibody constructs. Fc-fusion BiTE® antibody constructs (single-chain Fc BiTE® (triangles), hetero-Fc BiTE® (squares), canonical BiTE® (circles)) were applied to a Maxisorp plate (in serial dilutions) before incubation with pooled human serum and incubation with polyclonal mouse anti-human CC1q antibody visualized with a goat anti-mouse Fc-AP conjugate.

Fig. 5: Average PK profiles of four different pairs of BiTE®-HLE antibody fusion constructs following single dose administration to cynomolgus monkeys. For purposes of comparison, serum concentrations are normalized to the 15 mcg/kg dose and reported in nmol.

Fig. 6: Average PK profiles of nine different BiTE® antibody constructs, each fused to a half-life extending scFc component. For purposes of comparison, serum concentrations are normalized to the 15 mcg/kg dose and reported in nmol.

Fig. 7: bispecific scFc variants D9F (SEQ ID NO: 1453), T2G (SEQ ID NO: 1454), D3L (SEQ ID NO: 1455), T7I (SEQ ID NO: 1456) and K6C (SEQ ID NO: 1457) . A preferred antibody design of the present invention is set forth in SEQ ID NO: 1453.

Fig. 8: surface plasmon resonance (SPR) determination of binding to human FcRn. Constructs D9F, T2G, D3L, T7I and K6C were each tested for their ability to bind to human FcRn in Biacore experiments. Maximum binding during the injection phase was measured for all constructs in corresponding response units (RUs) equivalent to the increase in molecular weight on the FcRn-coated CM5 chip due to the presence of the bound construct. All constructs were measured in duplicate. The mean double determination values are shown in Fig. 8A and 8B.

Fig. 9: Constructs D9F, T2G, D3L, T7I and K6C and the human IgG1-kappa antibody MT201 were each examined for their ability to bind to human FcRn in SPR (Biacore) experiments. Maximum binding during the injection phase was measured for all constructs in corresponding response units (RUs) equivalent to the increase in molecular weight on the FcRn-coated CM5 chip due to the presence of the bound construct. All constructs were measured in duplicate. Duplicate means are shown, including error bars indicating standard deviation.

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Detailed Description of the Invention

In addition to significantly extending the half-life of the bispecific antibody constructs of the invention, the fusion of the specific Fc modality, i.e. the third domain of the invention is also responsible for the unexpectedly significant effect on the first and second binding domain of the antibody construct of the invention. Thus, while other half-life-extending modalities of T cell-engaging antibody constructs exhibit individual preferred features, the selection of the present specific Fc modality allows for the provision of bispecific molecules that exhibit a wide range of preferred characteristics of a functional molecular format and therefore enables the development promising pharmaceutical compositions.

Thus, the present invention provides an antibody construct comprising at least three domains, wherein the first domain binds to a target cell surface antigen, the second domain binds to an extracellular epitope of the human and/or Macaca CD3ε chain; and the third domain contains two polypeptide monomers, each of which contains a hinge domain, a CH2 domain and a CH3 domain, the two polypeptide monomers being fused to each other by a peptide linker.

The term antibody construct refers to a molecule whose structure and/or function is based on the structure and/or function of an antibody, such as a full-length or whole immunoglobulin molecule, and/or derived from heavy chain variable domains (VH) and/or light chain variable domains ( VL) antibody or fragment thereof. Therefore, the antibody construct is capable of binding to its specific target or antigen. In addition, the binding domain of an antibody construct in accordance with the invention contains the minimum structural requirements of the antibody that provide target binding. This minimum requirement may, for example, be determined by the presence of at least three light chain CDRs (i.e., VL region CDR1, CDR2, and CDR3) and/or three heavy chain CDRs (i.e., VH region CDR1, CDR2, and CDR3 ), preferably all six CDRs. An alternative approach to defining the minimum structural requirements of an antibody is to define the antibody epitope within the structure of the specific target, respectively, the protein domain of the target proteins constituting the epitope region (epitope cluster), or by specifying the specific antibody that competes for the epitope of the particular antibody. Antibodies on which the constructs of the invention are based include, for example, monoclonal, recombinant, chimeric, deimmunized, humanized and human antibodies.

The binding domain of an antibody construct according to the invention may, for example, contain the above CDR groups. Preferably, the CDRs are in the framework region of the antibody light chain variable region (VL) and the antibody heavy chain variable region (VH); however, it is not required to contain both of them. Fd fragments, for example, have two VH regions and often retain some of the antigen binding function of the intact antigen binding domain. Additional examples of the format of antibody fragments, antibody variants, or binding domains include (1) a Fab fragment, a monovalent fragment containing the VL, VH, CL, and CH1 domains; (2) fragment F(ab') ₂ , a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (3) Fd fragment containing two VH domains and a CH1 domain; (4) an Fv fragment containing the VL and VH domains of one arm of the antibody, (5) a dAb fragment (Ward et al., (1989) Nature 341:544-546) which contains a VH domain; (6) a dedicated complementarity determining region (CDR); and (7) a single chain Fv (scFv), the latter being preferred (eg, derived from a scFV library). Examples of embodiments of antibody constructs in accordance with the invention are described, for example, in WO 00/006605, WO 2005/040220, WO 2008/119567, WO 2010/037838, WO 2013/026837, WO 2013/026833, US 2014/0308285, US 2014/0302037, WO 2014/144722, WO 2014/151910 and WO 2015/048272.

Also within the definition of a binding domain or a domain that binds are full-length antibody fragments such as VH, VHH, VL, (s)dAb, Fv, Fd, Fab, Fab', F(ab') ₂ or rIgG (half-antibody). The antibody constructs of the invention may also contain modified antibody fragments, also called antibody variants, such as scFv, di-scFv or bi(s)scFv, scFv-Fc, scFv-zipper, scFab, Fab ₂ , Fab ₃ , diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFvs, tandem tri-scFvs, multibodies such as tribodies or tetrabodies, and single domain antibodies such as nanobodies or single variable domain antibodies containing only one variable domain, which can be VHH, VH or VL, which specifically bind an antigen or epitope independently of other V regions or domains.

As used herein, the terms single chain Fv, single chain antibodies, or scFv refer to single polypeptide chain antibody fragments that contain variable regions from both the heavy and light chains but lack constant regions. In general, a single-chain antibody additionally contains a polypeptide linker between the VH and VL domains, which allows the formation of the necessary structure that

- 3 043309 paradise allows antigen binding. Single chain antibodies are discussed in detail by Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315 (1994). Various methods for creating single-chain antibodies are known, including those described in US patents No. 4694778 and 5260203; publication of international patent application No. WO 88/01649; Bird (1988) Science 242:423–442; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; Ward et al. (1989) Nature 334:54454; Skerra et al. (1988) Science 242:1038–1041. In specific embodiments, single chain antibodies may also be bispecific, multispecific, human and/or humanized and/or synthetic.

In addition, the definition of the term antibody construct includes monovalent, bivalent and polyvalent/multivalent constructs and, therefore, bispecific constructs that specifically bind only two antigenic structures, as well as polyspecific/multispecific constructs that specifically bind more than two antigenic structures, e.g. four or more, via different binding domains. Moreover, the definition of the term antibody construct includes molecules consisting of only one polypeptide chain, as well as molecules consisting of more than one polypeptide chain, and the chains can be identical (homodimers, homotrimers or homo-oligomers) or different (heterodimers, heterotrimers or hetero-oligomers). . Examples of the antibodies defined above and their variants or derivatives are described, among other things, in Harlow and Lane, Antibodies a laboratory manual, CSHL Press (1988) and Using Antibodies: a laboratory manual, CSHL Press (1999), Kontermann and Dubel, Antibody Engineering, Springer, 2nd ed. 2010 and Little, Recombinant Antibodies for Immunotherapy, Cambridge University Press 2009.

As used herein, the term bispecific refers to an antibody construct that is at least bispecific, i.e. comprises at least a first binding domain and a second binding domain, wherein the first binding domain binds to one antigen or target (in this case: a cell surface target antigen) and the second binding domain binds to another antigen or target (in this case: CD3 ). Accordingly, the antibody constructs of the invention have specificity for at least two different antigens or targets. For example, the first domain preferably does not bind to an extracellular CD3ε epitope of one or more species described herein. The term cell surface target antigen refers to an antigenic structure expressed by a cell that is found on the cell surface, i.e. available for the antibody design described herein. It may be a protein, preferably an extracellular portion of a protein, or a carbohydrate structure, preferably a carbohydrate structure of a protein, such as a glycoprotein. Preferably it is a tumor antigen. The term bispecific antibody construct of the invention also includes multispecific antibody constructs, such as trispecific antibody constructs containing three binding domains, or constructs having more than three (eg, four, five...) specificities.

Given that the antibody constructs of the invention are (at least) bispecific, they are not naturally occurring and are markedly different from naturally occurring products. Therefore, a bispecific antibody or immunoglobulin construct is an artificial hybrid antibody or immunoglobulin having at least two different binding sites with different specificities. Bispecific antibody constructs can be prepared by a variety of methods, including hybridoma fusion or ligation of Fab' fragments. See, for example, Songsivilai & Lachmann, Clin. Exp. Immunol. 79:315-321 (1990).

The at least two binding domains and variable domains (VH/VL) of the antibody construct of the present invention may or may not contain peptide linkers (spacer peptides). The term peptide linker in accordance with this invention includes an amino acid sequence through which the amino acid sequences of one (variable and/or binding) domain and another (variable and/or binding) domain of an antibody construct are linked. Peptide linkers can also be used to fuse the third domain with other domains of the antibody construct of the invention. An important technical characteristic of such a peptide linker is that it has no polymerization activity. Suitable peptide linkers include those described in US patents 4751180 and 4935233 or WO 88/09344. Peptide linkers can also be used to attach other domains or modules or regions (such as half-life extending domains) to the antibody construct of the invention.

The antibody constructs of the invention are preferably in vitro generated antibody constructs. This term refers to an antibody design as defined above, in which all or part of the variable region (e.g., at least one CDR) is generated through selection in a non-immune cell, e.g., in vitro phage display, protein chip, or any other method, in in which candidate sequences can be examined for their ability to bind antigen. Preferably, the term excludes sequences created solely by genomic rearrangement in an animal immune cell. A recombinant antibody is an antibody created through the use of recombinant DNA technology or genetic engineering.

As used herein, the term monoclonal antibody (mAb) or monoclonal antibody construct refers to an antibody derived from a population of substantially homogeneous antibodies, i.e. the individual antibodies composing the population are identical except for possible natural mutations and/or post-translational modifications (eg, isomerization, amidation), which may be present in minor quantities. Monoclonal antibodies are highly specific, being directed against a single antigenic site or determinant on an antigen, as opposed to traditional (polyclonal) antibody preparations, which typically contain different antibodies directed against different determinants (or epitopes). In addition to their specificity, the advantage of monoclonal antibodies is that they are synthesized using a hybridoma culture, therefore, they do not contain impurities of other immunoglobulins. The term monoclonal indicates the nature of the antibody as being derived from an essentially homogeneous population of antibodies, and should not be taken as requiring the antibody to be produced by any particular method.

To obtain a monoclonal antibody preparation, any method that provides the production of antibodies using stable cultures of cell lines can be used. For example, monoclonal antibodies intended for use can be created by the hybridoma method first described by Koehler et al., Nature, 256: 495 (1975), or can be created by recombinant DNA methods (see, for example, US patent No. 4816567). Examples of additional techniques for producing human monoclonal antibodies include the trioma technique, the human B-cell hybridoma technique (Kozbor, Immunology Today 4 (1983), 72) and the EBV hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985), 77-96).

Hybridomas can then be screened using standard methods, such as enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance assay (BIACORE™), to identify one or more hybridomas that produce an antibody that specifically binds to a particular antigen. Any form of the corresponding antigen can be used as an immunogen, for example, recombinant antigen, natural forms, any variants or fragments thereof, as well as antigenic peptides thereof. Surface plasmon resonance, as used in the BIAcore system, can be used to enhance the activity of phage antibodies that bind to the cell surface epitope of a target antigen (Schier, Human Antibodies Hybridomas 7 (1996), 97-105; Malmborg, J. Immunol. Methods 183 (1995), 7-13).

Another typical method for producing monoclonal antibodies involves screening protein expression libraries, such as phage display or ribosome display libraries. Phage display is described, for example, in Ladner et al., US patent No. 5223409; Smith (1985) Science 228:1315-1317, Clackson et al., Nature, 352: 624-628 (1991) and Marks et al., J. Mol. Biol., 222: 581-597 (1991).

In addition to the use of display libraries, the corresponding antigen can be used to immunize a non-human animal, for example a rodent (such as a mouse, hamster, rabbit or rat). In one embodiment, the non-human animal contains at least a portion of a human immunoglobulin gene. For example, it is possible to construct mouse strains deficient in mouse antibody production with large fragments of human Ig (immunoglobulin) loci. Using hybridoma technology, it is possible to obtain and select antigen-specific monoclonal antibodies derived from genes with the required specificity. See, for example, XENOMOUSE™, Green et al. (1994) Nature Genetics 7:13-21, US 2003-0070185, WO 96/34096 and WO 96/33735.

A monoclonal antibody can also be obtained from a non-human animal and then modified, eg, humanized, deimmunized, chimeric, etc., using recombinant DNA technology known in the art. Examples of modified antibody constructs include humanized versions of non-human antibodies, affinity matured antibodies (see, for example, Hawkins et al. J. Mol. Biol. 254, 889-896 (1992) and Lowman et al., Biochemistry 30, 10832-10837 (1991)) and mutant antibodies with altered effector function(s) (see, for example, US Pat. No. 5,648,260, Kontermann and Dubel (2010), loc. cit. and Little (2009), loc. cit. .).

In immunology, affinity maturation is the process by which B cells produce antibodies with increased affinity for an antigen during an immune response. Upon repeated exposure to the same antigen, the host will produce antibodies with increasing affinity. Like its natural prototype, in vitro affinity maturation is based on the principles of mutation and selection. In vitro affinity maturation has been successfully used to optimize antibodies, antibody constructs, and antibody fragments. Random mutations within the CDR are introduced using radiation, chemical mutagens, or error-introducing PCR. In addition, genetic diversity can be increased by shuffling chains. Two or three rounds of mutation and selection using display methods such as phage display typically result in antibody fragments with affinities in the narrow nanomolar range.

A preferred type of variation in amino acid substitution antibody constructs involves substitution of one or more hypervariable region residues of a parent antibody (eg, a humanized or human antibody). In general, the resulting variants selected for further development should have improved biological properties relative to the parent antibody from which they are derived. A convenient way to create such replacement variants involves affinity maturation using phage display. Briefly, several regions of the hypervariable region (eg, 6-7 regions) are mutated to create all possible amino acid substitutions in each region. The antibody variants thus generated are displayed monovalently from the filamentous phage particles as fusion products with the M13 gene III product packaged within each particle. The phage displayed variants are then screened for their biological activity (eg, binding affinity) as described herein. To identify candidate hypervariable region regions for modification, alanine scanning mutagenesis can be performed to identify hypervariable region residues that contribute significantly to antigen binding. Alternatively or additionally, it may be useful to analyze the crystal structure of the antigen-antibody complex to determine points of contact between the binding domain and, for example, a human cell surface antigen target. Such contact residues and adjacent residues are candidates for replacement according to the techniques used herein. Once such variants are generated, the panel of variants is subjected to the screening described herein, and antibodies with superior properties in one or more relevant assays are selected for additional development.

Monoclonal antibodies and antibody constructs according to this invention include, in particular, chimeric antibodies (immunoglobulins), in which part of the heavy and/or light chain is identical or homologous with the corresponding sequences in antibodies derived from a particular species or belonging to a particular class or subclass of antibodies, then as the residue of the chain(s) is identical or homologous to the corresponding sequences in antibodies derived from another species or belonging to another class or subclass of antibodies, as well as fragments of such antibodies, if they exhibit the necessary biological activity (US patent No. 4816567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984). Chimeric antibodies of interest herein include primatized antibodies containing antigen binding variable domain sequences derived from a non-human primate (eg, Old World monkey, ape, etc.) and human constant region sequences. Many approaches have been described for generating chimeric antibodies. See, for example, Morrison et al., Proc. Natl. Acad. Sci U.S.A. 81:6851, 1985; Takeda et al., Nature 314:452, 1985, Cabilly et al., U.S. Patent no. 4,816,567; Boss et al., US Patent No. 4816397; Tanaguchi et al., EP 0171496; EP 0173494; and GB 2177096.

An antibody, antibody construct, antibody fragment or antibody variant can also be modified by specifically removing human T cell epitopes (a technique called deimmunization) by methods described, for example, in WO 98/52976 or WO 00/34317. Briefly, the variable domains of an antibody's heavy and light chain can be analyzed for the presence of peptides that bind to MHC class II; these peptides represent potential T cell epitopes (as defined in WO 98/52976 and WO 00/34317). A computer modeling approach called peptide pull-down can be used to identify potential T cell epitopes and, additionally, the human MHC class II binding peptide database can be searched for motifs present in the VH and VL sequences as described in WO 98/52976 and WO 00/34317. These motifs bind to any of the 18 major DR allotypes of MHC class II and thus constitute potential T cell epitopes. Identified potential T cell epitopes can be eliminated by substitution of a small number of amino acid residues in the variable domains or, preferably, by single amino acid substitutions. As a rule, conservative replacements are made. Often, but not exclusively, an amino acid typically present at that position in human germline antibody sequences may be used. Human germline sequences are described, for example, in Tomlinson, et al. (1992) J. Mol. Biol. 227:776-798; Cook, G.P. et al. (1995) Immunol. Today Vol. 16(5): 237242; and Tomlinson et al. (1995) EMBO J. 14: 14:4628-4638. The V BASE directory is a comprehensive directory of human immunoglobulin variable region sequences (compiled by Tomlinson, LA. et al. MRC Center for Protein Engineering, Cambridge, UK). These sequences can be used as a source of human sequences, such as framework regions or CDRs. Consensus human frameworks, such as those described in US Pat. No. 6,300,064, can also be used.

Humanized antibodies, antibody constructs, variants or fragments thereof (such as Fv,

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Fab, Fab', F(ab')2 or other antigen-binding antibody subsequences) are antibodies or immunoglobulins of mostly human sequence that contain minimal sequence(s) derived from non-human immunoglobulin. In general, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from the hypervariable region (also CDR) of the recipient are replaced by residues from the hypervariable region of a non-human (e.g., rodent) species (donor antibody), such as mouse, rat, hamster or rabbit, having the necessary specificity, affinity and capacity. In some cases, the Fv framework region (FR) residues of a human immunoglobulin are replaced by corresponding non-human residues. In addition, as used herein, humanized antibodies may also contain residues not found in either the recipient antibody or the donor antibody. These modifications are made to further improve and optimize the characteristics of the antibody. The humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc), typically from human immunoglobulin. For further details see Jones et al., Nature, 321: 522-525 (1986); Reichmann et al., Nature, 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2: 593-596 (1992).

Humanized antibodies or fragments thereof can be generated by replacing Fv variable domain sequences that are not directly involved in antigen binding with equivalent sequences from human Fv variable domains. Exemplary methods for creating humanized antibodies or fragments thereof are proposed in Morrison (1985) Science 229:1202-1207; in Oi et al. (1986) BioTechniques 4:214; and in US 5585089; US 5693761; US 5693762; US 5859205; and US 6,407,213. These methods involve isolating, processing and expressing nucleotide sequences that encode all or part of immunoglobulin Fv variable domains from at least one of the heavy or light chain. Such nucleic acids can be obtained from a hybridoma that produces an antibody against a given target, as described above, as well as from other sources. The recombinant DNA encoding the humanized antibody molecule can then be cloned into an appropriate expression vector.

Humanized antibodies can also be produced using transgenic animals, such as mice, that express human heavy and light chain genes but are unable to express endogenous murine immunoglobulin heavy and light chain genes. Winter describes a typical CDR grafting method that can be used to produce the humanized antibodies described herein (US Pat. No. 5,225,539). All of the CDRs of a particular human antibody may be replaced by at least a portion of the non-human CDR, or only some of the CDRs may be replaced by the non-human CDRs. It is only necessary to replace the number of CDRs required to bind the humanized antibody to a given antigen.

The humanized antibody can be optimized by introducing conservative substitutions, consensus sequence substitutions, germline substitutions and/or reverse mutations. Such altered immunoglobulin molecules can be generated using any of several techniques known in the art (eg, Teng et al., Proc. Natl. Acad. Sci. U.S.A., 80: 7308-7312, 1983; Kozbor et al., Immunology Today, 4: 7279, 1983; Olsson et al., Meth. Enzymol., 92: 3-16, 1982, and EP 239 400).

The term human antibody, human antibody construct, and human binding domain includes antibodies, antibody constructs, and binding domains having antibody regions, such as variable and constant regions or domains, that substantially correspond to human germline immunoglobulin sequences known in the art, including, for example, those described in Kabat et al. (1991) (loc. cit.). Human antibodies, antibody constructs, or binding domains of the invention may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced through random or site-specific mutagenesis in vitro or through somatic mutation in vivo), for example, in the CDR, and in particular in CDR3. Human antibodies, antibody constructs, or binding domains may contain at least one, two, three, four, five or more positions replaced by an amino acid residue not encoded by a human germline immunoglobulin sequence. However, as used herein, the definition of human antibodies, antibody constructs and binding domains also includes fully human antibodies that contain only artificially and/or genetically unaltered human antibody sequences, such as those that can be produced using technologies or systems such as Xenomouse. Preferably, the fully human antibody does not contain amino acid residues not encoded by human germline immunoglobulin sequences.

In some embodiments, the antibody constructs of the invention are isolated or substantially pure antibody constructs. When used to describe antibody constructs presented herein, isolated or substantially pure means an antibody construct that has been identified, separated, and/or isolated from a component of the environment in which it is produced. Preferably, the antibody construct is unrelated or substantially unrelated

- 7 043309 is combined with all other components from the environment in which it is produced. Contaminants in the production environment, such as those left over from recombinant transfected cells, are materials that tend to interfere with the diagnostic or therapeutic use of the polypeptide, and may include enzymes, hormones, and other protein or non-protein solutes. The antibody constructs may, for example, constitute at least about 5% or at least about 50% by weight of the total protein in a given sample. It is understood that the isolated protein may range from 5 to 99.9% by weight of the total protein content depending on the circumstances. The polypeptide can be produced at a substantially higher concentration by using an inducible or high expression promoter so that it is produced at an increased concentration level. This definition includes the production of an antibody construct in a wide range of organisms and/or host cells that are known in the art. In preferred embodiments, the antibody construct is purified (1) to an extent sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence using a rotating beaker sequencer, or (2) to homogeneity by SDS-PAGE in non-reducing or reducing conditions using Coomassie blue or, preferably, silver staining. Typically, the antibody construct is obtained through at least one purification step.

The term binding domain in connection with this invention characterizes a domain that (specifically) binds/interacts with/recognizes a given target epitope or target site on target molecules (antigens), for example, CD33 and CD3, respectively. The structure and function of the first binding domain (recognizing CD33) and preferably also the structure and/or function of the second binding domain (recognizing CD3) are based on the structure and/or function of an antibody, for example, a full-length or whole immunoglobulin molecule, and/or derived from the variable domains of a severe chain (VH) and/or light chain variable domains (VL) of an antibody or fragment thereof. Preferably, the first binding domain is characterized by the presence of three light chain CDRs (ie VL region CDR1, CDR2 and CDR3) and/or three heavy chain CDRs (ie VH region CDR1, CDR2 and CDR3). The second binding domain preferably also contains the minimum structural requirements of the antibody that provide target binding. More preferably, the second binding domain contains at least three light chain CDRs (ie, VL region CDR1, CDR2 and CDR3) and/or three heavy chain CDRs (ie, VH region CDR1, CDR2 and CDR3). It is intended that the first and/or second binding domain be produced or obtained by phage display or library screening methods rather than by grafting CDR sequences from a pre-existing (monoclonal) antibody into the framework.

In accordance with the present invention, the binding domains are in the form of one or more polypeptides. Such polypeptides may contain protein portions and non-protein portions (eg, chemical linkers or chemical cross-linking agents such as glutaraldehyde). Proteins (including fragments thereof, preferably biologically active fragments, and peptides typically having less than 30 amino acids) contain two or more amino acids linked together by a covalent peptide bond (resulting in a chain of amino acids).

As used herein, the term polypeptide describes a group of molecules that typically consists of more than 30 amino acids. Polypeptides can further form multimers such as dimers, trimers and higher oligomers, i.e. consisting of more than one polypeptide molecule. The polypeptide molecules forming such dimers, trimers, etc., may or may not be identical. The corresponding higher order structures of such multimers are respectively called homo- or heterodimers, homo- or heterotrimers, etc. An example of a heteromultimer is an antibody molecule, which in its natural form consists of two identical light polypeptide chains and two identical heavy polypeptide chains. The terms peptide, polypeptide and protein also refer to naturally modified peptides/polypeptides/proteins in which the modification is due, for example, to post-translational modifications such as glycosylation, acetylation, phosphorylation and the like. As used herein, the peptide, polypeptide or protein may also be chemically modified, for example pegylated. Such modifications are well known in the art and are described below herein.

Preferably, the binding domain that binds to the target cell surface antigen and/or the binding domain that binds to CD3ε is/are human binding domains. Antibodies and antibody constructs containing at least one human binding domain avoid some of the problems associated with antibodies or antibody constructs that have non-human, e.g., rodent (e.g., mouse, rat, hamster, or rabbit), variable and/or constant regions. The presence of such proteins from a rodent may result in rapid clearance of antibodies or antibody constructs or may result in the generation of an immune response against the antibody or antibody construct in a patient. To avoid the use of rodent-derived antibodies or antibody constructs,

- 8 043309 it is possible to create human or fully human antibodies/antibody constructs by introducing into a rodent the function of a human antibody so that the rodent produces fully human antibodies.

The ability to clone and recover human loci on the order of millions of base pairs in YAC and introduce them into the mouse germline provides an effective approach for studying the functional components of very large or coarsely mapped loci and for generating useful models of human diseases. In addition, the use of such technology to replace murine loci with their human equivalents may provide unique information about the expression and regulation of human gene products during development, their interactions with other systems, and their role in disease induction and progression.

An important practical application of this strategy is the humanization of the murine humoral immune system. Introduction of human immunoglobulin (Ig) loci into mice in which endogenous Ig genes have been inactivated provides an opportunity to study the mechanisms underlying programmed expression and assembly of antibodies, as well as their role in B cell development. In addition, such a strategy could provide an ideal source for producing fully human monoclonal antibodies (mAbs), a key point toward fulfilling the promise of antibody-based therapies for human diseases. Fully human antibodies or antibody constructs are expected to minimize the immunogenic and allergic responses associated with murine or mouse-derived mAbs and therefore enhance the efficacy and safety of the administered antibodies/antibody constructs. The use of fully human antibodies or antibody constructs can be expected to provide significant benefits in the treatment of chronic and recurrent human diseases such as inflammation, autoimmunity and cancer, which require repeated administration of compounds.

One approach toward this goal has been to construct mouse strains deficient in mouse antibody production with large fragments of human Ig loci, with the expectation that such mice will produce a broad repertoire of human antibodies in the absence of mouse antibodies. Large human Ig fragments must maintain a wide diversity of variable genes as well as proper regulation of antibody production and expression. By using a mouse apparatus to enhance the diversity and selection of antibodies and the absence of immunological tolerance to human proteins, the reconstituted repertoire of human antibodies in these mouse strains should result in high-affinity antibodies against the antigen of interest, including human antigens. Using hybridoma technology, antigen-specific human mAbs with the required specificity can be easily produced and screened. This general strategy was demonstrated in connection with the creation of the first XenoMouse mouse strains (see Green et al. Nature Genetics 7:13-21 (1994)). XenoMouse strains were constructed with yeast artificial chromosomes (YACs) containing 245-kb fragments. and 190 kb. germline configurations of the human heavy chain locus and the kappa light chain locus, respectively, which contained internal variable and constant region sequences. Human Ig-containing YACs were found to be compatible with the mouse system in terms of both rearrangement and antibody expression, and were able to replace inactivated mouse Ig genes. This has been demonstrated by their ability to induce B cell development, produce a human adult repertoire of fully human antibodies, and generate antigen-specific human mAbs. These results also suggest that the introduction of larger portions of human Ig loci containing more V genes, additional regulatory elements and human Ig constant regions can recapitulate essentially the complete repertoire characteristic of the human humoral response to infection and immunization. The work of Green et al. Was recently expanded to include more than approximately 80% of the human antibody repertoire by introducing YAC fragments on the order of a million base pairs of the germline configuration of the human heavy chain locus and the kappa light chain locus, respectively. See Mendez et al. Nature Genetics 15:146-156 (1997) and US Patent Application Serial No. 08/759620.

Preparation of XenoMouse mice is further discussed and described in US Patent Applications Serial No. 07/466,008, Serial No. 07/610,515, Serial No. 07/919,297, Serial No. 07/922,649, Serial No. 08/031,801, Serial No. 08/112 848, serial no. 08/234 145, serial no. 08/376 279, serial no. 08/430 938, serial no. 08/464 584, serial no. 08/464 582, serial no. 08/463 191, serial no. 08 /462 837, serial No. 08/486 853, serial No. 08/486 857, serial No. 08/486 859, serial No. 08/462 513, serial No. 08/724 752, and serial No. 08/759 620; and US patents No. 6162963; 6150584; 6114598; 6075181 and 5.939598, and Japanese patents No. 3,068,180 B2, 3,068,506 B2 and 3,068,507 B2. See also Mendez et al. Nature Genetics 15:146–156 (1997) and Green and Jakobovits J. Exp. Med. 188:483-495 (1998), EP 0 463 151 B1, WO 94/02602, WO 96/34096, WO 98/24893, WO 00/76310 and WO 03/47336.

In an alternative approach, others, including GenPharm International, Inc., have used a minilocus approach. In the minilocus approach, the exogenous Ig locus is mimicked by incorporating pieces (individual genes) from the Ig locus. Thus, one or more VH genes, one or more DH genes, one or more JH genes, a mu constant region and a second constant region (preferably a gamma constant region) form a construct for insertion into an animal. This approach is described in US Patent No. 5545807 by Surani et al. and US patents No. 5545806; 5625825; 5625126; 5633425; 5661016; 5770429; 5789650; 5814318; 5877397; 5874299; and 6,255,458, each to Lonberg and Kay, US Patent Nos. 5,591,669 and 6,023,010 to Krimpenfort and Berns, US Patent No. 5,612,205; 5721367; and 5,789,215 to Berns et al., and US Patent No. 5,643,763 to Choi and Dunn, and US Patent Application to GenPharm International, Serial No. 07/574,748, Serial No. 07/575,962, Serial No. 07/810,279, Serial No. 07/853 408, serial no. 07/904 068, serial no. 07/990 860, serial no. 08/053 131, serial no. 08/096 762, serial no. 08/155 301, serial no. 08/161 739, serial no. 08 /165 699, serial number 08/209 741. Also see EP 0 546 073 B1, WO 92/03918, WO 92/22645, WO 92/22647, WO 92/22670, WO 93/12227, WO 94/00569, WO 94/25585, WO 96/14436, WO 97/13852 and WO 98/24884 and US Patent No. 5981175. See also Taylor et al. (1992), Chen et al. (1993), Tuaillon et al. (1993), Choi et al. (1993), Lonberg et al. (1994), Taylor et al. (1994) and Tuaillon et al. (1995), Fishwild et al. (1996).

Kirin also demonstrated the creation of human antibodies using mice injected with large pieces of chromosomes or entire chromosomes via microcellular infusion. See European Patent Applications Nos. 773,288 and 843,961. Xenerex Biosciences is developing technology to potentially create human antibodies. In this technology, SCID mice are regenerated using human lymphatic cells, such as B and/or T cells. Mice are then immunized with an antigen and can mount an immune response against that antigen. See US Patents No. 5,476,996; 5698767 and 5958765.

Human anti-mouse antibody (HAMA) responses have led the industry to create chimeric or otherwise humanized antibodies. However, it is expected that some human anti-chimeric antibody (HACA) responses will be observed, particularly with chronic or multi-dose administration of the antibody. Thus, it would be desirable to provide antibody constructs containing a human binding domain against a cell surface target antigen and a human binding domain against CD3ε to refute doubts regarding and/or the results of the HAMA or NASA responses.

The terms (specifically) binds to, (specifically) recognizes, (specifically) targets and (specifically) reacts with mean in accordance with this invention that the binding domain interacts or specifically interacts with a given epitope or a given target site on target molecules (antigens) , in this case: target cell surface antigen and CD3ε, respectively.

The term epitope refers to the region on an antigen to which a binding domain, such as an antibody or immunoglobulin, or a derivative, fragment or variant of an antibody or immunoglobulin, specifically binds. An epitope is antigenic and therefore, as used herein, the term epitope is sometimes referred to as an antigenic structure or antigenic determinant. Thus, the binding domain is the site of interaction with the antigen. It is also intended that said binding/interaction determines specific recognition.

Epitopes can be formed by both adjacent amino acids and non-adjacent amino acids located nearby as a result of protein folding into a tertiary structure. A linear epitope is an epitope in which the primary amino acid sequence contains a recognizable epitope. A linear epitope typically contains at least 3 or at least 4, and more often at least 5, or at least 6, or at least 7, such as about 8 to about 10 amino acids in a unique sequence.

A conformational epitope, as opposed to a linear epitope, is an epitope in which the primary sequence of amino acids constituting the epitope is not the sole defining component of the recognized epitope (eg, an epitope in which the primary sequence of amino acids is not necessarily recognized by the binding domain). Typically, a conformational epitope contains a greater number of amino acids compared to a linear epitope. With respect to conformational epitope recognition, the binding domain recognizes the three-dimensional structure of the antigen, preferably a peptide or protein or fragment thereof (in the context of the present invention, the antigenic structure for one of the binding domains is contained within the target cell surface antigen protein). For example, when a protein molecule folds to form a three-dimensional structure, the specific amino acids and/or polypeptide backbone that form the conformational epitope are located nearby, allowing the epitope to be recognized by an antibody. Methods for determining the conformation of epitopes include, but are not limited to, X-ray crystallography, two-dimensional nuclear magnetic resonance spectroscopy (2D-RMP), and site-directed spin label and electron paramagnetic resonance (EPR) spectroscopy.

The epitope mapping method is described as follows: When a region (contiguous region

- 10 043309 amino acids) in a human cell surface target antigen protein is replaced/replaced by the corresponding region of a non-human and non-primate cell surface target antigen (e.g. mouse cell surface target antigen, although others such as chicken, rat are also allowed , hamster, rabbit, etc.), a reduction in the binding of the binding domain is expected to occur if the binding domain is not cross-reactive with the non-human and non-primate cell surface target antigen employed. Said reduction is preferably at least 10, 20, 30, 40 or 50%; more preferably at least 60, 70 or 80%, and most preferably 90, 95 or even 100% compared to binding to the corresponding region in the human cell surface antigen target protein, wherein binding to the corresponding human cell surface antigen target protein is established like 100%. The above human cell surface antigen target/non-human cell surface target antigen chimeric structures are intended to be expressed in CHO cells. It is also contemplated that human cell surface antigen/non-human cell surface target antigen chimeric structures are fused to the transmembrane domain and/or cytoplasmic domain of a different membrane-bound protein such as EpCAM.

In an alternative or complementary epitope mapping method, multiple truncated versions of the extracellular domain of a human cell surface antigen target can be generated to determine the specific region that is recognized by the binding domain. These truncated versions remove different extracellular domains/subdomains or regions of the target cell surface antigen in stages, starting at the N-terminus. It is contemplated that truncated versions of the target cell surface antigen can be expressed in CHO cells. It is also contemplated that truncated versions of the target cell surface antigen can be fused to the transmembrane domain and/or cytoplasmic domain of a different membrane-bound protein such as EpCAM. It is also contemplated that truncated versions of the target cell surface antigen may include a signal peptide domain at the N-terminus, for example, a signal peptide derived from a murine IgG heavy chain signal peptide. It is further contemplated that truncated versions of the target cell surface antigen may include a v5 domain at the N-terminus (after the signal peptide), which allows confirmation of their correct expression on the cell surface. It is expected that a reduction or cessation of binding will be observed for those truncated versions of the target cell surface antigen that no longer include the region of the target cell surface antigen recognized by the binding domain. The reduction in binding is preferably at least 10, 20, 30, 40, 50%; more preferably at least 60, 70, 80%, and most preferably 90, 95 or even 100%, with binding to the entire cell surface human antigen target protein (or extracellular region or domain thereof) set to 100.

An additional method for determining the contribution of a particular target cell surface antigen residue to recognition by an antibody construct or binding domain is the alanine scan (see, e.g., Morrison KL & Weiss GA. Cur Opin Chem Biol. 2001 Jun; 5(3):302-7) , in which each residue intended for analysis is replaced by alanine, for example, by site-directed mutagenesis. Alanine is used for its bulky, chemically inert, methyl functional group, which also mimics the secondary structure found in many other amino acids. Bulky amino acids such as valine or isoleucine can sometimes be used in cases where the size of the mutated residue must be maintained. Alanine scanning is a proven technology that has been used for a long time.

An interaction between a binding domain and an epitope or epitope-containing region means that the binding domain exhibits acceptable affinity for the epitope/epitope-containing region in a particular protein or antigen (in this case: cell surface target antigen and CD3, respectively) and, generally does not demonstrate significant reactivity with proteins or antigens other than the target cell surface antigen and CD3. Acceptable affinity includes binding with an affinity of about 10 ^-6 M (KD) or higher. Preferably, binding is considered specific when the binding affinity is from about 10 ^-12 to 10 ^-8 M, from 10 ^-12 to 10 ^-9 M, from 10 ^-12 to 10 ^-10 M, from 10 ^-11 to 10 ^-8 M, preferably from about 10 ^-11 to 10 ^-9 M. Whether a specific binding domain reacts or binds to a target can be easily verified, inter alia, by comparing the reaction of said binding domain to a target protein or antigen with the reaction of said binding domain to proteins or antigens other than target cell surface antigens or CD3. Preferably, the binding domain of the invention does not bind substantially or substantially to proteins or antigens other than the target cell surface antigen or CD3 (i.e., the first binding domain is incapable of binding to proteins other than the target cell surface antigen, and the second binding domain domain is incapable of binding to proteins other than CD3). An implied characteristic of the antibody constructs of this invention is that they have superior affinity characteristics compared to other HLE formats. Therefore, such superior affinity implies an extended half-life in vivo. The longer half-life of the antibody constructs of the present invention may reduce the duration and frequency of administration, which generally has the effect of improving patient compliance with the treatment regimen. This is extremely important since the antibody constructs of this invention are extremely useful for severely debilitated or even multimorbid cancer patients.

The term substantially/substantially does not bind or is unable to bind means that the binding domain of the present invention does not bind a protein or antigen other than the target cell surface antigen or CD3, i.e. does not demonstrate reactivity of more than 30%, preferably no more than 20%, more preferably no more than 10%, in particular preferably no more than 9, 8, 7, 6 or 5% with proteins or antigens other than the target cell surface antigen or CD3, with binding to the target cell surface antigen or CD3, respectively, set to 100%.

Specific motifs in the amino acid sequence of the binding domain and the antigen are believed to influence specific binding. Thus, binding is achieved as a result of their primary, secondary and/or tertiary structure, as well as as a result of secondary modifications of these structures. The specific interaction of an antigen interaction site with its specific antigen may result in simple binding of the site to the antigen. Moreover, the specific interaction of the antigen interaction site with its specific antigen may alternatively or additionally lead to the initiation of a signal, for example, due to the induction of a change in antigen conformation, oligomerization of the antigen, etc.

The term variable refers to portions of antibody or immunoglobulin domains that exhibit sequence variability and that are involved in determining the specificity and binding affinity of a particular antibody (ie, variable domain(s)). Pairing together of a variable heavy chain (VH) and a variable light chain (VL) results in the formation of a single antigen-binding site.

Variability is not evenly distributed among antibody variable domains; it is concentrated in subdomains of each of the heavy and light chain variable regions. These subdomains are called hypervariable regions or complementarity determining regions (CDRs). The more conserved (ie, non-hypervariable) portions of the variable domains are called framework regions (FRMs or FRs) and provide a framework for the six CDRs in three dimensions to form the antigen-binding surface. Each of the naturally occurring heavy and light chain variable domains contains four FRM regions (FR1, FR2, FR3 and FR4) adopting a largely β-sheet configuration, connected by three hypervariable regions that form loops connecting, and in some cases forming part of β-sheet structure. The hypervariable regions on each chain are held together in close proximity to the FRM and, together with the hypervariable regions from the other chain, contribute to the formation of the antigen binding site (see Kabat et al., loc. cit.).

The terms CDR and multiple form of CDR refer to complementarity determining regions, of which three determine the binding pattern of the light chain variable region (CDRL1, CDR-L2 and CDR-L3) and three determine the binding pattern of the heavy chain variable region (CDR-H1, CDR-H2 and CDR-H3). CDRs contain the majority of residues responsible for the specific interaction of an antibody with an antigen and, therefore, contribute to the functional activity of the antibody molecule: they are the main determinants of antigen specificity.

The precise definition of the boundaries and dimensions of a CDR is subject to different classifications and numbering systems. Therefore, CDRs may be designated according to Kabat, Chothia, contact, or any other boundary definitions, including the numbering system described herein. Despite their differing boundaries, each of these systems has some degree of overlap in what constitutes the so-called hypervariable regions within the variable sequences. Consequently, CDR definitions under these systems may differ in length and boundary portions relative to the adjacent frame region. See, for example, Kabat (an approach based on interspecies sequence variability), Chothia (an approach based on crystallographic studies of antigen-antibody complexes), and/or MacCallum (Kabat et al., loc. cit.; Chothia et al., J. Mol Biol, 1987, 196: 901-917; and MacCallum et al., J Mol Biol, 1996, 262: 732). Another standard for characterizing the antigen-binding site is the AbM definition used in Oxford Molecular's AbM antibody modeling software. See, for example, Protein Sequence and Structure Analysis of Antibody Variable Domains. B: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Rontermann, R., Springer-Verlag, Heidelberg). When two residue identification techniques identify residues from overlapping but not identical regions, they can be combined to identify a hybrid CDR. In this case, numbering in accordance with the so-called Kabat system is preferable.

Typically, CDRs form a loop structure, which can be classified as a canonical structure. The term canonical structure refers to the basic chain conformation that the antigen-binding (CDR) loops adopt. From comparative structural studies, five of the six antigen-binding loops were found to have only a limited set of available conformations. Each canonical structure can be characterized by the torsion angle of the polypeptide backbone. Consequently, corresponding loops among antibodies may have very similar three-dimensional structures, despite high amino acid variability in most parts of the loops (Chothia and Lesk, J. Mol. Biol., 1987, 196: 901; Chothia et al., Nature, 1989, 342 : 877; Martin and Thornton, J Mol Biol, 1996, 263: 800). In addition, there is a relationship between the structure adopted by the loop and the amino acid sequences surrounding it. The conformation of a particular canonical class is determined by the length of the loop and the amino acid residues located at key positions within the loops, as well as within the conserved framework region (i.e., outside the loop). Assignment to a particular canonical class can therefore be made based on the presence of these key amino acid residues.

The term canonical structure may also include factors associated with the linear sequence of an antibody, such as those cataloged by Kabat (Kabat et al., loc. cit.). The Kabat numbering scheme is a widely accepted standard for numbering the amino acid residues of an antibody variable domain in a sequential manner and is the preferred scheme used in this invention, which is also mentioned elsewhere in this document. Additional structure factors can also be used to determine the canonical structure of an antibody. For example, those differences that are not fully reflected in the Kabat numbering can be described using the numbering system of Chothia et al. and/or identified using other techniques, such as crystallography and two- or three-dimensional computer modeling.

Accordingly, a given antibody sequence can be assigned to a canonical class, which allows, among other things, the identification of corresponding chassis sequences (eg, based on the need to include a variety of canonical structures in the library). Kabat numbering of antibody amino acid sequences and structural factors described by Chothia et al., loc. cit., and their implications for the design of canonical aspects of antibody structure are described in the literature. The subunit structures and three-dimensional configurations of various classes of immunoglobulins are well known in the art. For an overview of antibody structure, see Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, eds. Harlow et al., 1988.

Light chain CDR3 and particularly heavy chain CDR3 may constitute the most important determinants in antigen binding within the light and heavy chain variable regions. In some antibody designs, the heavy chain CDR3 constitutes the major contact area between the antigen and the antibody. In vitro selection schemes in which only CDR3 is varied can be used to vary the binding properties of an antibody or to determine which residues contribute to antigen binding. Therefore, CDR3 is generally the greatest source of molecular diversity within the binding region of an antibody. For example, H3 can be as short as two amino acid residues or over 26 amino acids long.

In classical full-length immunoglobulin, each light (L) chain is linked to a heavy (H) chain by a single covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds, depending on the H chain isotype. The CH domain closest to VH is usually designated CH1. Constant (C) domains are not directly involved in antigen binding but exhibit various effector functions such as antibody-dependent cell-mediated cytotoxicity and complement activation. The Fc region of an antibody is located within the constant domains of the heavy chain and, for example, is capable of interacting with surface-located Fc receptors.

The sequence of antibody genes after assembly and somatic mutation is highly variable and these variable genes are estimated to encode 10 ¹⁰ different antibody molecules (Immunoglobulin Genes, ^2nd ed., eds. Jonio et al., Academic Press, San Diego, CA, 1995). Accordingly, the immune system provides a certain repertoire of immunoglobulins. The term repertoire refers to at least one nucleotide sequence derived in whole or in part from at least one sequence encoding at least one immunoglobulin. The sequence(s) can be obtained by in vivo rearrangement of the V, D and J segments of the heavy chains and the V and J segments of the light chains. Alternatively, the sequence(s) can be obtained from the cell in response to which the rearrangement occurs, for example, in vitro stimulation. Alternatively, part or all of the sequence(s) can be obtained through DNA splicing, nucleotide synthesis, mutagenesis and other methods, see, for example, US patent 5565332. The repertoire may include only one sequence or may include multiple sequences, including those located in genetically diverse collection.

In connection with this invention, the term Fc portion or Fc monomer means a polypeptide containing at least one domain having the function of a CH2 domain and at least one domain having the function of a CH3 domain of an immunoglobulin molecule. As is evident from the term Fc monomer,

- 13 043309 the polypeptide containing these CH domains is a polypeptide monomer. The Fc monomer may be a polypeptide comprising at least a portion of an immunoglobulin constant region excluding the first domain of an immunoglobulin heavy chain constant region (CH1), but retaining at least a functional portion of one CH2 domain and a functional portion of one CH3 domain, wherein the CH2 domain is amino-terminal to the CH3 domain. In a preferred aspect of this definition, the Fc monomer may be a polypeptide constant region comprising a portion of an Ig-Fc hinge region, a CH2 region, and a CH3 region, the hinge region being amino-terminal to the CH2 domain. The hinge region of the present invention is understood to promote dimerization. Such Fc polypeptide molecules can be prepared, for example and without limitation, by digestion of the immunoglobulin region with papain (resulting, of course, in a dimer of two Fc polypeptides). In another aspect of this definition, an Fc monomer may be a polypeptide region comprising a portion of a CH2 region and a CH3 region. Such Fc polypeptide molecules can be prepared, for example and without limitation, by pepsin digestion of an immunoglobulin molecule. In one embodiment, the polypeptide sequence of the Fc monomer is substantially similar to the sequence of the Fc polypeptide: IgG1 Fc region, IgG ₂ Fc region, IgG ₃ Fc region, IgG4 Fc region, IgM Fc region, IgA Fc region, IgD Fc region and Fc regions of IgE. (See, for example, Padlan, Molecular Immunology, 31(3), 169-217 (1993)). Due to some variation between immunoglobulins, and for clarity only, the Fc monomer refers to the last two domains of the immunoglobulin heavy chain constant region of IgA, IgD and IgG and the last three domains of the immunoglobulin heavy chain constant region of IgE and IgM. As mentioned, the Fc monomer may also contain a flexible hinge region located N-terminal to these domains. In the case of IgA and IgM, the Fc monomer may contain a J chain. In the case of IgG, the Fc portion contains the immunoglobulin domains CH2 and CH3 and the hinge region between the first two domains and CH2. Although the boundaries of the Fc portion may vary, an example of a human IgG heavy chain Fc portion containing a functional hinge region, CH2 and CH3 domains may, for example, by definition contain residues from D231 (the hinge domain - corresponding to D234 in Table 1 below) to P476 , respectively L476 (in the case of IgG ₄ ), the carboxy end of the CH3 domain, where the numbering is given in accordance with Kabat. Two Fc moieties or two Fc monomers fused to each other via a peptide linker define a third domain of the antibody construct of the invention, which may also be defined as a scFc domain.

In one embodiment, the scFc domain described herein, or the Fc monomers fused to each other, is contemplated to be present only in the third domain of the antibody construct.

In accordance with the present invention, the hinge region of an IgG can be defined by analogy using Kabat numbering, as shown in table. 1. In accordance with the above, it is understood that the hinge domain/hinge region according to the present invention contains amino acid residues corresponding to the IgG1 sequence region from D234 to P243 according to Kabat numbering. Likewise, the hinge domain/hinge region of the present invention is intended to contain or consist of the IgG1 hinge sequence DKTHTCPPCP (SEQ ID NO: 1449) (corresponding to the region D234 to P243 as shown in Table 1 below, variations of said sequence are also intended , provided that the hinge region continues to stimulate dimerization). In a preferred embodiment, the glycosylation site at position 314 of the Kabat CH2 domains in the third domain of the antibody construct is removed by substitution N314X, where X is any amino acid except Q. The substitution is preferably N314G. In a more preferred embodiment of the invention, said CH2 domain further contains the following substitutions (positions according to Kabat): V321C and R309C (these substitutions introduce an intradomain cysteine disulfide bridge at positions 309 and 321 according to Kabat).

It is also contemplated that the third domain of the antibody construct of the invention contains or consists of, in order from amino terminus to carboxy terminus: DKTHTCPPCP (SEQ ID NO: 1449) (i.e., hinge region) -CH2-CH3 linker - DKTHTCPPCP (SEQ ID NO: 1449) (ie, hinge region) CH2-CH3. The peptide linker in the above antibody construct is in a preferred embodiment characterized by the amino acid sequence Gly-Gly-Gly-Gly-Ser, i.e. Gly ₄ Ser (SEQ ID NO: 1), or polymers thereof, i.e. (Gly ₄ Ser) _x where x is an integer equal to 5 or more (for example, 5, 6, 7, 8, etc. or more), with 6 ((Gly ₄ Ser) ₆ ) being preferred . Said design may further comprise the above substitutions N314X, preferably N314G, and/or additional substitutions V321C and R309C. In a preferred embodiment of the antibody constructs of the invention as defined previously, the second domain is intended to bind to an extracellular epitope of the human and/or Macaca CD3ε chain.

- 14 043309

Table 1

Numbering of amino acid residues of the hinge region according to Kabat

IMGT numbering for the hinge area Amino acid translation of IgGi Kabat numbering 1 (E) 226 2 R 227 3 TO 228 4 S 232 5 With 233 6 D 234 7 TO 235 8 T 236 9 N 237 10 T 238 eleven WITH 239 12 R 240 13 R 241 14 With 242 15 R 243

In further embodiments of the present invention, the hinge domain/hinge region comprises or consists of an IgG2 subtype hinge sequence ERKCCVECPPCP (SEQ ID NO: 1450), an IgG ₃ subtype sequence ELKTPLDTTHTCPRCP (SEQ ID NO: 1451) or ELKTPLGDTTHTCPRCP (SEQ ID NO: 1458), and /or IgG4 subtype sequence ESKYGPPCPSCP (SEQ ID NO: 1452). The hinge sequence of the IgG1 subtype may be: EPKSCDKTHTCPPCP (as shown in Table 1 and SEQ ID NO: 1459).

Thus, these main hinge regions are also intended in the context of this invention.

The position and sequence of the CH2 domain of IgG and the CD3 domain of IgG can be determined by analogy using Kabat numbering, as shown in Table. 2:

table 2

Numbering of amino acid residues in the CH2 and CH3 region of IgG according to Kabat ak ak

Subtype Numbering Numbering broadcast broadcast

IgG СН2 according to Kabat СНЗ according to Kabat

СН2 СНЗ

igGi ARK.. ... HOW 244... ...360 GQP... ...PGK 361... ...478 IgG ₂ ARR... ...KTK 244... ...360 GQP... ...PGK 361... ...478 IgG ₃ ARK.. ...KTK 244... ...360 GQP... ...PGK 361... ...478 IgG ₄ ARK.. ... HOW 244... ...360 GQP... ...LGK 361... ...478

In one embodiment, the bolded amino acid residues in the CH3 domain of the first or both Fc monomers are deleted.

The peptide linker by which the polypeptide monomers (Fc portion or Fc monomer) of the third domain are fused to each other preferably contains at least 25 amino acid residues (25, 26, 27, 28, 29, 30, etc.). More preferably, the peptide linker contains at least 30 amino acid residues (30, 31, 32, 33, 34, 35, etc.). It is also preferred that the linker contains up to 40 amino acid residues, more preferably up to 35 amino acid residues, most preferably exactly 30 amino acid residues. In a preferred embodiment, such a peptide linker is characterized by the amino acid sequence Gly-Gly- 15 043309

Gly-Gly-Ser, i.e. Gly ₄ Ser (SEQ ID NO: 1), or polymers thereof, i.e. (Gly ₄ Ser) _x , where x is an integer equal to 5 or more (for example, 6, 7 or 8). Preferably the integer is 6 or 7, more preferably the integer is 6.

In the event that a linker is used to fuse a first domain to a second domain, or a first or second domain to a third domain, the linker is preferably of length and sequence sufficient to ensure that each of the first and second domains can independently maintain its differential specificity binding. In the case of peptide linkers that connect at least two binding domains (or two variable domains) in the antibody construct of the invention, peptide linkers that contain only a few amino acid residues, for example 12 amino acid residues, are preferred. Thus, peptide linkers of 12, 11, 10, 9, 8, 7, 6 or 5 amino acid residues are preferred. The intended peptide linker of less than 5 amino acids contains 4, 3, 2 or one amino acid, with Gly-rich linkers being preferred. A preferred embodiment of the peptide linker for fusing the first and second domains is set forth in SEQ ID NO: 1. A preferred embodiment of the peptide linker for fusing the second and third domains is a (Gly) ₄ linker, respectively a _G4 linker.

A particularly preferred single amino acid in the context of the above-described peptide linker is Gly. Accordingly, said peptide linker may consist of a single amino acid Gly. In a preferred embodiment of the invention, the peptide linker is characterized by the amino acid sequence Gly-Gly-Gly-Gly-Ser, i.e. Gly ₄ Ser (SEQ ID NO: 1), or polymers thereof, i.e. (Gly ₄ Ser) _x , where x is an integer equal to 1 or more (for example, 2 or 3). Preferred linkers are given in SEQ ID NO: 1 to 12. The characteristics of the specified peptide linker, which include the absence of stimulation of the formation of secondary structures, are known in the art and are described, for example, in Dall'Acqua et al. (Biochem. (1998) 37, 9266-9273), Cheadle et al. (Mol Immunol (1992) 29, 21-30) and Raag and Whitlow (FASEB (1995) 9(1), 73-80). Preferred are peptide linkers that, among other things, do not promote the formation of any secondary structures. The connection of these domains with each other can be ensured, for example, through genetic engineering, as described in the examples. Methods for preparing fused and operably linked bispecific single-strand constructs and expressing them in mammalian cells or bacteria are well known in the art (eg, WO 99/54440 or Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2001).

In a preferred embodiment of the antibody construct of the present invention, the first and second domains form the antibody construct in a format selected from the group consisting of (scFv) ₂ , scFv single domain mAb, diabody, and oligomers of any of these formats.

In accordance with a particularly preferred embodiment of the invention and as described in the accompanying examples, the first and second domains of the antibody construct of the invention are a bispecific single chain antibody construct, more preferably a bispecific single chain Fv (scFv). Although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined, using recombinant methods, by a synthetic linker - as previously described herein - which allows them to be produced as a single protein chain in which the VL regions and VH are paired to form a monovalent molecule; see, for example, Huston et al. (1988) Proc. Natl. Acad. Sci USA 85:5879–5883). These antibody fragments are prepared using conventional techniques known to those skilled in the art, and the fragments are assessed for function in the same manner as full-length antibodies. Therefore, a single chain variable fragment (scFv) is a fusion protein of the heavy chain (VH) and light chain (VL) variable regions of immunoglobulins, typically linked by a short linker peptide of about ten to about 25 amino acids in length, preferably about 15 to 20 amino acids. Typically the linker is loaded with glycine for flexibility and serine or threonine for solubility and can connect the N-terminus of VH to the C-terminus of VL, or vice versa. This protein retains the specificity of the original immunoglobulin, despite the removal of constant regions and the addition of a linker.

Bispecific single chain antibody constructs are known in the art and are described in WO 99/54440, Mack, J. Immunol. (1997), 158, 3965-3970, Mack, PNAS, (1995), 92, 7021-7025, Kufer, Cancer Immunol. Immunother., (1997), 45, 193-197, Loffler, Blood, (2000), 95, 6, 2098-2103, Bruhl, Immunol., (2001), 166, 2420-2426, Kipriyanov, J. Mol. Biol., (1999), 293, 41-56. Techniques for producing single-chain antibodies (see, among others, US Pat. No. 4,946,778, Kontermann and Dubel (2010), loc. cit. and Little (2009), loc. cit.) can be adapted to produce single-chain antibody constructs that specifically recognize a selected ( s) target(s).

Bivalent (also called divalent) or bispecific single chain variable fragments (bi-scFv or di-scFv, having the format (scFv) ₂ can be constructed by linking two scFv molecules (for example, with linkers, as described previously). If the two scFv molecules have

- 16 043309 the same binding specificity, the resulting (scFv)2 molecule will preferably be called bivalent (ie it has two valencies for one target epitope). If two scFv molecules have different binding specificities, the resulting (scFv) ₂ molecule will preferably be called bispecific. Linking can be accomplished by producing a single peptide chain with two VH regions and two VL regions, resulting in tandem scFvs (see, for example, Kufer P. et al., (2004) Trends in Biotechnology 22(5):238-244 ). Another possibility is to create scFv molecules with linker peptides that are too short to hold two variable regions together (for example, about five amino acids), which forces the scFv to dimerize. This type is known as diabodies (see, for example, Hollinger, Philipp et al., (July 1993) Proceedings of the National Academy of Sciences of the United States of America 90(14):6444-8).

In accordance with this invention, any of the first, second, or first and second domains may constitute a single domain antibody, respectively a variable domain, or at least part of a CDR of a single domain antibody. Single domain antibodies contain only one (monomeric) antibody variable domain that is capable of selectively binding to a specific antigen, independent of other V regions or domains. The first single-domain antibodies were constructed from heavy-chain-only antibodies found in camelids, called VHH fragments. Cartilaginous fish also have heavy chain-only antibodies (IgNARs) from which single-domain antibodies called V _NAR fragments can be produced. An alternative approach is to break the dimeric variable domains from conventional immunoglobulins, such as those from humans or rodents, into monomers, thereby producing VH or VL as a single domain Ab. Although most research on single-domain antibodies to date has been based on heavy chain variable domains, light chain-derived nanobodies have also been shown to specifically bind to target epitopes. Examples of single domain antibodies are called sdAbs, nanobodies, or single variable domain antibodies.

Therefore, single domain (mAb)2 is a monoclonal antibody construct consisting of (at least) two single domain monoclonal antibodies that are individually selected from the group consisting of VH, VL, VHH and V _NAR . The linker preferably takes the form of a peptide linker. Likewise, a scFv single-domain mAb is a monoclonal antibody construct consisting of at least one single-domain antibody as described above and one scFv molecule as described above. Again, the linker is preferably in the form of a peptide linker.

Whether an antibody construct competes for binding with another given antibody construct can be determined in a competition assay such as a competitive ELISA or a cell competition assay. Avidin-coated microparticles (granules) can also be used. Similar to the avidin-coated ELISA plate, when reacting with a biotinylated protein, each of these beads can be used as a substrate for the assay. The antigen is applied to the bead and then the first antibody is pre-coated. A second antibody is added and the presence of any additional binding is determined. Possible means for data acquisition include flow cytometry.

T cells or T lymphocytes are a type of lymphocyte (which is itself a type of white blood cell) that plays a major role in cell-mediated immunity. There are several subsets of T cells, each with a distinct function. T cells can be distinguished from other lymphocytes such as B cells and NK cells by the presence of the T cell receptor (TCR) on the cell surface. TCR is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules and consists of two different protein chains. In 95% of T cells, TCR consists of an alpha (α) and beta (β) chain. When a TCR comes into contact with an antigenic peptide and an MHC (peptide/MHC complex), the T cell is activated through a series of biochemical events mediated by associated enzymes, co-receptors, specialized adapter molecules, and activated or released transcription factors.

The CD3 receptor complex is a protein complex and consists of four chains. In mammals, the complex contains a CD3y (gamma) chain, a CD3δ (delta) chain, and two CD3ε (epsilon) chains. These chains bind to the T-cell receptor (TRC) and the so-called ζ (zeta) chain to form the T-cell receptor-CD3 complex and generate an activation signal in T lymphocytes. The CD3y (gamma), CD3δ (delta), and CD3ε (epsilon) chains are highly related cell surface proteins of the immunoglobulin superfamily, containing a single extracellular immunoglobulin domain. The intracellular tails of CD3 molecules contain one conserved motif, known as the immunoreceptor tyrosine activating motif or ITAM for short, which is important for the signaling capabilities of TRC. The CD3 epsilon molecule is a polypeptide that in humans is encoded by the CD3E gene, which is located on chromosome 11. The most preferred CD3 epsilon epitope is found within amino acid residues 1 to 27 of the extracellular domain of human CD3 epsilon. It is understood that the antibody constructs of the present invention are generally and advantageously less likely to exhibit nonspecific T cell activation, which

- 17 043309 is undesirable in specific immunotherapy. This leads to a reduced risk of side effects.

Redirected lysis of target cells by recruitment of T cells by a multispecific, at least bispecific antibody construct involves formation of a cytolytic synapse and delivery of perforin and granzymes. Recruited T cells are capable of serial lysis of target cells and are not affected by immunosurveillance evasion mechanisms that interfere with the processing and presentation of peptide antigens or clonal differentiation of T cells; see for example WO 2007/042261.

Cytotoxicity mediated by the antibody constructs of the invention can be determined in various ways. The effector cells may be, for example, enriched (human) CD8-positive T cells or unstimulated (human) peripheral blood mononuclear cells (PBMCs). If the target cells are derived from or expressed in macaques or are transfected with a macaque cell surface target antigen that is bound by the first domain, the effector cells must also be derived from macaques, for example, a macaque T cell line such as 4119LnPx. The target cells must express (at least the extracellular domain) a target cell surface antigen, for example, a human or macaque cell surface target antigen. The target cells may be a cell line (such as CHO) stably or transiently transfected with a target cell surface antigen, for example, a human or macaque cell surface target antigen. Alternatively, the target cells may be a naturally expressing cell line that is positive for a target cell surface antigen. EC ₅₀ values are generally expected to be lower for target cell lines expressing higher levels of the target cell surface antigen on the cell surface. The ratio between effector cells and target cells (E:M) is usually about 10:1, but can also vary. The cytotoxic activity of bispecific antibody constructs to cell surface antigen and CD3 targets can be determined in a ⁵¹ Cr release assay (incubation time about 18 hours) or a FACS-based cytotoxicity assay (incubation time about 48 hours). Modifications to the incubation time (cytotoxic reaction) in the assay are also possible. Other methods for determining cytotoxicity are well known in the art and include the MTT or MTS assay, ATP-based assays including bioluminescence assay, sulforhodamine B (SRB) assay, WST assay, clonogenic assay, and ECIS technology.

Cytotoxic activity mediated by bispecific antibody constructs to cell surface antigen and CD3 of the present invention is preferably determined in a cell-based cytotoxicity assay. It can also be determined in a ⁵¹ Cr release assay. It is represented by the EC ₅₀ value, which corresponds to the half-maximal effective concentration (the concentration of the antibody construct that induces a cytotoxic response halfway between the initial and maximum levels). Preferably, the _EC50 value of the bispecific antibody constructs to the cell surface antigen and CD3 target is <5000 pM or <4000 pM, more preferably <3000 pM or <2000 pM, even more preferably <1000 pM or <500 pM, even more preferably <400 pM or <300 pM, even more preferably <200 pM, even more preferably <100 pM, even more preferably <50 pM, even more preferably <20 pM or <10 pM and most preferably <5 pM.

The above EC50 values can be determined in different assays. One skilled in the art will be aware that the EC50 value can be expected to be lower when stimulated/enriched CD8+ T cells are used as effector cells compared to unstimulated PBMCs. In addition, EC ₅₀ values can be expected to be lower when target cells express high amounts of target cell surface antigen compared to low levels of target expression. For example, when stimulated/enriched CD8+ T cells are used as effector cells (and target cell surface antigen-transfected cells such as CHO cells or target cell surface antigen-positive human cell lines are used as target cells), the EC50 value of a bispecific antibody construct to a cell surface antigen and CD3 target is preferably <1000 pM, more preferably <500 pM, even more preferably <250 pM, even more preferably <100 pM, even more preferably <50 pM, even more preferably < 10 pM and most preferably <5 pM. When human PBMCs are used as effector cells, the EC ₅₀ value of the bispecific antibody construct to the cell surface antigen and CD3 target is preferably <5000 pM or <4000 pM (particularly when the target cells are positive for the target cell surface antigen cell lines), more preferably <2000 pM (particularly when the target cells are cells transfected with a cell surface antigen, such as CHO cells), more preferably <1000 pM or <500 pM, even more preferably <200 pM, even more preferably <150 pM, even more

- 18 043309 preferably <100 pM and most preferably <50 pM or less. When a macaque T cell line such as LnPx4119 is used as the effector cells, and a macaque cell surface antigen-transfected cell line such as CHO cells is used as the target cell line, the EC ₅₀ value of the bispecific antibody construct to the target cell surface antigen and CD3 is preferably <2000 pM or <1500 pM, more preferably <1000 pM or <500 pM, even more preferably <300 pM or <250 pM, even more preferably <100 pM, and most preferably <50 pM.

Preferably, the bispecific cell surface antigen and CD3 antibody constructs of the present invention do not induce/mediate lysis or substantially do not induce/mediate lysis of target cell surface antigen negative cells, such as CHO cells. The term does not induce lysis, substantially does not induce lysis, does not mediate lysis, or substantially does not mediate lysis means that the antibody construct of the present invention does not induce or mediate lysis of more than 30%, preferably no more than 20%, preferably no more than 10%, in features preferably no more than 9, 8, 7, 6 or 5% cell surface antigen-negative cells, with lysis of the target cell surface antigen-positive human cell line set at 100%. This typically corresponds to antibody construct concentrations of up to 500 nM. One skilled in the art will know how to detect cell lysis without any extra effort. In addition, specific instructions for determining cell lysis are provided herein.

The difference between the cytotoxic activity of the monomeric and dimeric isoforms of individual bispecific antibody constructs to the target cell surface antigen and CD3 is called the activity difference. This difference in activity can be calculated, for example, as the ratio between the EC ₅₀ values of the monomeric and dimeric forms of the molecule. The difference in activity of the bispecific antibody constructs to the cell surface antigen and CD3 target according to the present invention is preferably <5, more preferably <4, even more preferably <3, even more preferably <2 and most preferably <1.

The first and/or second (or any additional) binding domain of the antibody construct of the invention is preferably cross-species specific for members of the mammalian primate class. Cross-species specific CD3 binding domains are described, for example, in WO 2008/119567. In accordance with one embodiment of the invention, the first and/or second binding domain, in addition to binding to human cell surface antigen target and human CD3, respectively, also binds to primate cell surface antigen/CD3 target antigen, including but not limited to New World primates (such as Callithrix jacchus, Saguinus Oedipus or Saimiri sciureus), Old World primates (such as baboons and macaques), gibbons and non-human homininae.

In one embodiment of the antibody construct of the invention, the first domain binds to a human cell surface target antigen and further binds to a macaque cell surface target antigen, such as a Macaca fascicularis cell surface target antigen, and more preferably to a macaque cell surface target antigen expressed on macaque cell surfaces. The affinity of the first domain for the target macaque cell surface antigen is preferably <15 nM, more preferably <10 nM, even more preferably <5 nM, even more preferably <1 nM, even more preferably <0.5 nM, even more preferably < 0.1 nM and most preferably <0.05 nM or even <0.01 nM.

Preferably, the difference in affinity of the antibody constructs of the invention for binding macaque cell surface target antigen compared to human cell surface target antigen [ma cell surface target antigen:hu cell surface target antigen] (determined, for example, in the BiaCore assay or Scatchard's analysis) is <100, preferably <20, more preferably <15, more preferably <10, even more preferably <8, more preferably <6 and most preferably <2. Preferred difference ranges in affinity of the antibody constructs of the invention for binding to a macaque cell surface target antigen compared to a human cell surface target antigen are from 0.1 to 20, more preferably from 0.2 to 10, even more preferably from 0.3 to 6, even more preferably 0.5 to 3 or 0.5 to 2.5, and most preferably 0.5 to 2 or 0.6 to 2.

The second (binding) domain of the antibody construct of the invention binds to human CD3 epsilon and/or Masasa CD3 epsilon. In a preferred embodiment of the invention, the second domain further binds to CD3 epsilon of Callithrix jacchus, Saguinus Oedipus or Saimiri sciureus. Callithrix jacchus and Saguinus oedipus are New World primates belonging to the family Callitrichidae, while Saimiri sciureus is a New World primate belonging to the family Cebidae.

For the construction of an antibody according to the present invention, it is preferred that the second domain

- 19 043309 which binds to the extracellular epitope of human and/or Macaca CD3, contained a VL region containing CDR-L1, CDR-L2 and CDR-L3 selected from:

(a) CDR-L1 given in SEQ ID NO: 27 in WO 2008/119567, CDR-L2 given in SEQ ID NO:

in WO 2008/119567, and CDR-L3 given in SEQ ID NO: 29 in WO 2008/119567;

(b) CDR-L1 given in SEQ ID NO: 117 in WO 2008/119567, CDR-L2 given in SEQ ID NO: 118 in WO 2008/119567, and CDR-L3 given in SEQ ID NO: 119 in WO 2008/119567; and (c) CDR-L1 given in SEQ ID NO: 153 in WO 2008/119567, CDR-L2 given in SEQ ID NO: 154 in WO 2008/119567, and CDR-L3 given in SEQ ID NO: 155 in WO 2008/119567.

Also in a preferred embodiment of the antibody construct of the present invention, preferably the second domain that binds to the extracellular epitope of human CD3 and/or Macaca contains a VH region containing CDR-H1, CDR-H2 and CDR-H3 selected from:

(a) CDR-H1 given in SEQ ID NO: 12 in WO 2008/119567, CDR-H2 given in SEQ ID NO: 13 in WO 2008/119567, and CDR-H3 given in SEQ ID NO: 14 in WO 2008/119567;

(b) CDR-H1 given in SEQ ID NO: 30 in WO 2008/119567, CDR-H2 given in SEQ ID NO: 31 in WO 2008/119567, and CDR-H3 given in SEQ ID NO: 32 in WO 2008/119567;

(c) CDR-H1 given in SEQ ID NO: 48 in WO 2008/119567, CDR-H2 given in SEQ ID NO: 49 in WO 2008/119567, and CDR-H3 given in SEQ ID NO: 50 in WO 2008/119567;

(d) CDR-H1 given in SEQ ID NO: 66 in WO 2008/119567, CDR-H2 given in SEQ ID NO: 67 in WO 2008/119567, and CDR-H3 given in SEQ ID NO: 68 in WO 2008/119567;

(e) CDR-H1 given in SEQ ID NO: 84 in WO 2008/119567, CDR-H2 given in SEQ ID NO: 85 in WO 2008/119567, and CDR-H3 given in SEQ ID NO: 86 in WO 2008/119567;

(f) CDR-H1 given in SEQ ID NO: 102 in WO 2008/119567, CDR-H2 given in SEQ ID NO: 103 in WO 2008/119567, and CDR-H3 given in SEQ ID NO: 104 in WO 2008/119567;

(g) CDR-H1 given in SEQ ID NO: 120 in WO 2008/119567, CDR-H2 given in SEQ ID NO: 121 in WO 2008/119567, and CDR-H3 given in SEQ ID NO: 122 in WO 2008/119567;

(h) CDR-H1 given in SEQ ID NO: 138 in WO 2008/119567, CDR-H2 given in SEQ ID NO: 139 in WO 2008/119567, and CDR-H3 given in SEQ ID NO: 140 in WO 2008/119567;

(i) CDR-H1 given in SEQ ID NO: 156 in WO 2008/119567, CDR-H2 given in SEQ ID NO: 157 in WO 2008/119567, and CDR-H3 given in SEQ ID NO: 158 in WO 2008/119567; and (j) CDR-H1 given in SEQ ID NO: 174 in WO 2008/119567, CDR-H2 given in SEQ ID NO: 175 in WO 2008/119567, and CDR-H3 given in SEQ ID NO: 176 in WO 2008/119567.

In a preferred embodiment of the antibody construct of the invention, the three VL CDR groups described above are combined with the ten VH CDR groups described above within the second binding domain to produce (30) groups each containing CDR-L 1-3 and CDR-H 1- 3.

For the antibody design of the present invention, it is preferred that the second domain that binds CD3 comprises a VL region selected from the group consisting of the VL regions set forth in SEQ ID NOs: 17, 21, 35, 39, 53, 57, 71, 75, 89, 93, 107, 111, 125, 129, 143, 147, 161, 165, 179 or 183 in WO 2008/119567, or as given in SEQ ID NO: 13.

It is also preferred that the second domain that binds CD3 comprises a VH region selected from the group consisting of the VH regions set forth in SEQ ID NO: 15, 19, 33, 37, 51, 55, 69, 73, 87 , 91, 105, 109, 123, 127, 141, 145, 159, 163, 177 or 181 in WO 2008/119567, or set forth in SEQ ID NO: 14.

More preferably, the antibody construct of the present invention is characterized by a second domain that binds to CD3, comprising a VL region and a VH region selected from the group consisting of:

(a) the VL region given in SEQ ID NO: 17 or 21 in WO 2008/119567, and the VH region given in SEQ ID NO: 15 or 19 in WO 2008/119567;

(b) the VL region given in SEQ ID NO: 35 or 39 in WO 2008/119567, and the VH region given in SEQ ID NO: 33 or 37 in WO 2008/119567;

(c) the VL region given in SEQ ID NO: 53 or 57 in WO 2008/119567, and the VH region given in SEQ ID NO: 51 or 55 in WO 2008/119567;

(d) the VL region given in SEQ ID NO: 71 or 75 in WO 2008/119567, and the VH region given in SEQ ID NO: 69 or 73 in WO 2008/119567;

(e) the VL region given in SEQ ID NO: 8 9 or 93 in WO 2008/119567, and the VH region given in SEQ ID NO: 87 or 91 in WO 2008/119567;

(f) the VL region given in SEQ ID NO: 107 or 111 in WO 2008/119567, and the VH region given in SEQ ID NO: 105 or 109 in WO 2008/119567;

(g) the VL region given in SEQ ID NO: 125 or 129 in WO 2008/119567, and the VH region given in SEQ ID NO: 123 or 127 in WO 2008/119567;

(h) the VL region given in SEQ ID NO: 143 or 147 in WO 2008/119567, and the VH region given in SEQ ID NO: 141 or 145 in WO 2008/119567;

- 20 043309 (i) the VL region given in SEQ ID NO: 161 or 165 in WO 2008/119567, and the VH region given in SEQ ID NO: 159 or 163 in WO 2008/119567; and (j) the VL region given in SEQ ID NO: 179 or 183 in WO 2008/119567, and the VH region given in SEQ ID NO: 177 or 181 in WO 2008/119567.

Also in connection with the design of the antibody of the present invention, it is preferred that the second domain that binds CD3 comprises the VL region set forth in SEQ ID NO: 13 and the VH region set forth in SEQ ID NO: 14.

In a preferred embodiment of the antibody design of the present invention, the first and/or second domain have the following format. Pairs of VH regions and VL regions are in single chain antibody (scFv) format. The VH and VL regions are arranged in the order VH-VL or VL-VH. Preferably, the VH region is located N-terminal to the linker sequence and the VL region is located C-terminal to the linker sequence.

A preferred embodiment of the above-described antibody construct of the present invention is characterized by a second domain that binds to CD3 containing an amino acid sequence selected from the group consisting of SEQ ID NO: 23, 25, 41, 43, 59, 61, 77, 79, 95, 97, 113, 115, 131, 133, 149, 151, 167, 169, 185 or 187 of WO 2008/119567 or SEQ ID NO: 15.

Covalent modifications of antibody constructs are also included within the scope of this invention and are generally, but not always, carried out after translation. For example, several types of covalent modifications of the antibody construct are introduced into the molecule by reacting specific amino acid residues of the antibody construct with an organic derivatizing agent that is capable of reacting with selected side chains of the N- or C-terminal residues.

Cysteinyl residues are most often reacted with α-haloacetates (and corresponding amines) such as chloroacetic acid or chloroacetamide to give carboxymethyl or carboxyamidomethyl derivatives. Cysteinyl residues are also derivatized by reaction with bromotrifluoroacetone, a-bromo-b-(5-imidozoyl)propionic acid, chloroacetyl phosphate, N-alkylmaleimides, 3-nitro-2-pyridyl disulfide, methyl 2-pyridyl disulfide, pchloro-mercuric benzoate, 2-chloro-mercury 4-nitrophenol or chloro-7-nitrobenzo-2-oxa-1,3-diazole.

The histidyl residues are derivatized by reaction with diethyl pyrocarbonate at pH 5.5-7.0, since this agent is relatively specific for the histidyl side chain. Para-bromophenacyl bromide is also used; the reaction is preferably carried out in 0.1 M sodium cacodylate at pH 6.0. Lysinyl residues and amino-terminal residues are reacted with succinic anhydride or anhydrides of other carboxylic acids. Derivatization with these agents results in the charge of lysinyl residues being reversed. Other suitable agents for derivatizing alpha-amino residues include imidoesters such as picolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride; trinitrobenzenesulfonic acid; O-methylisourea; 2,4-pentanedione; and a transaminase-catalyzed reaction with glyoxylate.

Arginyl residues are modified by reacting with one of several conventional reagents, including phenylglyoxal, 2,3-butanedione, 1,2-cyclohexanedione, and ninhydrin. Derivatization of arginine residues requires the reaction to be carried out under alkaline conditions due to the high pKa value of the guanidine functional group. In addition, these reagents can react with lysine groups as well as the epsilon amino group of arginine.

Specific modification of tyrosyl residues can be carried out, and of particular interest is the introduction of spectral labels into tyrosyl residues by reaction with aromatic diazonium compounds or tetranitromethane. Nacetylimidizole and tetranitromethane are most often used to obtain molecules of O-acetyltyrosyl and 3-nitro derivatives, respectively. Tyrosyl residues are iodinated using ¹²⁵ I or ¹³¹ I to obtain labeled proteins for use in radioimmunoassays, the chloramine T method described above being suitable.

Carboxyl side groups (aspartyl or glutamyl) are selectively modified by reaction with carbodiimides (R'-N=C=N--R'), where R and R' are optionally different alkyl groups such as 1-cyclohexyl-3- (2-morpholinyl-4-ethyl)carbodiimide or 1ethyl-3-(4-azonia-4,4-dimethylpentyl)carbodiimide. In addition, aspartyl and glutamyl residues are converted to asparaginyl and glutaminyl residues by reaction with ammonium ions.

Derivatization with bifunctional agents is used to cross-link the antibody constructs of this invention to a water-insoluble immobilizing matrix or surface for use in various methods. Commonly used cross-linking agents include, for example, 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, 4-azidosalicylic acid esters, homobifunctional imido esters, including disuccinimidyl esters such as 3,3'- 21 043309 dithiobis(succinimidylpropionate), and bifunctional maleimides such as bis-K-maleimido-1,8octane. Derivatizing agents such as methyl 3-[(p-azidophenyl)dithio]propioimidate provide photoactivatable intermediates that are capable of cross-linking in the presence of light. Alternatively, reactive water-insoluble matrices such as cyanogen bromide-activated carbohydrates and reactive substrates described in US Pat. No. 3,969,287 are used to immobilize proteins; 3691016; 4195128; 4247642; 4229537 and 4330440.

Glutaminyl and asparaginyl residues are often deamidated to the corresponding glutamyl and aspartyl residues, respectively. Alternatively, these residues are deamidated under mild acidic conditions. Any form of these residues falls within the scope of this invention.

Other modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of α-amino groups of lysine, arginine and histidine side chains (I.e. Creighton, Proteins: Structure and Molecular Properties, W. H. Freeman & Co., San Francisco, 1983, pp. 79-86), acetylation of the N-terminal amine and amidation of any C-terminal carboxyl group.

Another type of covalent modification of antibody constructs included within the scope of this invention involves changing the glycosylation profile of a protein. As is known in the art, glycosylation profiles can depend on both the sequence of the protein (eg, the presence or absence of specific amino acid glycosylation residues, as discussed below) and the host cell or organism in which the protein is produced. Specific expression systems are discussed below.

Glycosylation of polypeptides is usually N-linked or O-linked. N-linked glycosylation refers to the addition of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are recognition sequences for enzymatically attaching a carbohydrate moiety to the asparagine side chain. Thus, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the addition of one of the sugars N-acetylgalactosamine, galactose or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used.

The addition of glycosylation sites to an antibody construct is conveniently accomplished by altering the amino acid sequence so that it contains one or more of the tripeptide sequences described above (for N-linked glycosylation sites). The change can also be made by adding or replacing one or more serine or threonine residues in the start sequence (for O-linked glycosylation sites). Conveniently, the amino acid sequence of the antibody construct is preferably altered through changes at the DNA level, in particular by mutating the DNA encoding the polypeptide at preselected bases so as to create codons that will be translated into the required amino acids.

Another means of increasing the number of carbohydrate components on an antibody construct is to chemically or enzymatically couple the glycosides to the protein. The advantage of these procedures is that they do not require protein production in the host cell, where the potential for N- and O-linked glycosylation exists. Depending on the conjugation method used, sugar (a) can be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as in cysteine, (d) free hydroxyl groups such as in serine , threonine or hydroxyproline, (e) aromatic residues such as those in phenylalanine, tyrosine or tryptophan, or (f) the amide group of glutamine. These methods are described in WO 87/05330 and in Aplin and Wriston, 1981, CRC Crit. Rev. Biochem., pp. 259-306.

Removal of carbohydrate components present in the original antibody construct can be accomplished chemically or enzymatically. Chemical deglycosylation requires exposing the protein to a trifluoromethanesulfonic acid compound or an equivalent compound. This treatment results in the elimination of most or all sugars except the linking sugar (N-acetylglucosamine or N-acetylgalactosamine), while leaving the polypeptide intact. Chemical deglycosylation is described in Hakimuddin et al., 1987, Arch. Biochem. Biophys. 259:52 and in Edge et al., 1981, Anal. Biochem. 118:131. Enzymatic cleavage of carbohydrate components on polypeptides can be achieved by the use of various endo- and exoglycosidases, as described in Thotakura et al., 1987, Meth. Enzymol. 138:350. Glycosylation at potential glycosylation sites can be prevented by the use of the compound tunicamycin, as described in Duskin et al., 1982, J. Biol. Chem. 257:3105. Tunicamycin blocks the formation of protein-N-glycoside bonds.

Other modifications to the antibody design are also provided herein. For example, another type of covalent modification of an antibody construct involves linking the antibody construct to various non-protein polymers, including, but not limited to, various polyols such as polyethylene glycol, polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, as described in US Pat. No. 4,640,835 ; 4496689; 4301144;

- 22 043309

4670417; 4791192 or 4179337. In addition, as is known in the art, amino acid substitutions can be made at various positions in the antibody construct, for example, to facilitate the addition of polymers such as PEG.

In some embodiments, covalent modification of the antibody constructs of the invention includes the addition of one or more tags. The labeling group can be coupled to the antibody construct via spacer stalks of varying lengths to reduce potential steric mismatch. Various protein labeling methods are known in the art that can be used in the practice of this invention. The term label or labeling group refers to any detectable label. In general, labels are divided into many classes depending on the analysis method in which they are supposed to be identified; the following examples include, but are not limited to:

a) isotopic tracers, which may be radioactive or heavy isotopes, such as radioisotopes or radionuclides (for example, ³ H, ¹⁴ C, ¹⁵ N, ³⁵ S, ⁸⁹ Zr, ⁹⁰ Y, ⁹⁹ Tc, ⁿ¹ In, ¹²⁵ I, ¹³¹ I);

b) magnetic tags (eg magnetic particles);

c) redox active components;

d) optical dyes (including, but not limited to, chromophores, luminophores and fluorophores), such as fluorescent groups (e.g. FITC, rhodamine, lanthanide complex phosphors), chemiluminescent groups and fluorophores, which may be low molecular weight fluorophores, and protein fluorophores;

e) enzymatic groups (eg horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase);

f) biotinylated groups;

g) predefined polypeptide epitopes recognized by the secondary reporter (eg, paired leucine zipper sequences, binding sites for secondary antibodies, metal binding domains, epitope tags, etc.).

A fluorescent label refers to any molecule that can be detected due to its inherent fluorescent properties. Suitable fluorescent labels include, but are not limited to, fluorescein, rhodamine, tetramethylrhodamine, eosin, erythrosine, coumarin, methylcoumarins, pyrene, malachite green, stilbene, Lucifer yellow, Cascade Blue J, Texas Red, IAEDANS, EDANS, BODIPY FL, LC Red 640, Su 5, Su 5.5, LC Red 705, Oregon green, Alexa-Fluor dyes (Alexa Fluor 350, Alexa Fluor 430, Alexa Fluor 488, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, Alexa Fluor 680), blue cascade, yellow cascade and R-phycoerythrin (PE) (Molecular Probes, Eugene, OR), FITC, rhodamine and Texas red (Pierce, Rockford, IL), Cy5, Cy5.5, Cy7 ( Amersham Life Science, Pittsburgh, PA). Suitable optical dyes, including fluorophores, are described in the Molecular Probes Handbook by Richard P. Haugland.

Suitable protein fluorescent tags also include, but are not limited to, green fluorescent protein, including Renilla, Ptilosarcus or Aequorea species (Chalfie et al., 1994, Science 263:802-805), USFP (Clontech Laboratories, Inc., accession no. Genbank U55762), blue fluorescent protein (BFP, Quantum Biotechnologies, Inc. 1801 de Maisonneuve Blvd. West, 8th Floor, Montreal, Quebec, Canada H3H 1J9; Stauber, 1998, Biotechniques 24:462-471; Heim et al., 1996 , Curr. Biol. 6:178-182), enhanced yellow fluorescent protein (UYFP, Clontech Laboratories, Inc.), luciferase (Ichiki et al., 1993, J. Immunol. 150:5408-5417), β-galactosidase ( Nolan et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:26032607) and Renilla (WO 92/15673, WO 95/07463, WO 98/14605, WO 98/26277, WO 99/49019, US patents No. 5292658; 5418155; 5683888; 5741668; 5777079; 5804387; 5874304; 5876995; 5925558).

The antibody construct of the invention may also contain additional domains that, for example, assist in isolating the molecule or are relevant to tailoring the pharmacokinetic profile of the molecule. Domains that assist in the isolation of the antibody construct can be selected from peptide motifs or secondary components that can be captured in the isolation process, for example, in a recovery column. Non-limiting embodiments of such additional domains include peptide motifs known as Myc tag, HAT tag, HA tag, TAP tag, GST tag, chitin binding domain (CBD tag), maltose binding domain (MBP tag), Flag tag, Strep tag and its variants (for example, StrepII tag) and His tag. The antibody constructs described herein, characterized by certain CDRs, may contain a His tag domain, which is generally known as a repeat of consecutive His residues in the amino acid sequence of a molecule, preferably five, and more preferably six His residues (hexa-histidine). The His tag may be located, for example, at the N or C terminus of the antibody construct, preferably it is located at the C terminus. Most preferably, a hexa-histidine tag (HHHHHH) (SEQ ID NO: 16) is linked via a peptide bond to the C terminus of the antibody construct of the invention. In addition, the PLGA-PEG-PLGA conjugate system can be combined with a poly-histidine tag for sustained release applications and improved pharmacokinetic profile.

- 23 043309

Modifications to the amino acid sequences of the antibody constructs described herein are also contemplated. For example, it may be necessary to improve the binding affinity and/or other biological properties of the antibody construct. Variants of the amino acid sequences of antibody constructs are obtained by introducing appropriate nucleotide changes into the nucleic acids of antibody constructs, or by peptide synthesis. All amino acid sequence modifications described below should result in an antibody construct that retains the requisite biological activity (binding to target cell surface antigen and CD3) of the unmodified parent molecule.

The term amino acid or amino acid residue generally refers to an amino acid having a definition known in the art, such as an amino acid selected from the group consisting of: alanine (Ala or A); arginine (Arg or R); asparagine (Asn or N); aspartic acid (Asp or D); cysteine (Cys or C); glutamine (Gln or Q); glutamic acid (Glu or E); glycine (Gly or G); histidine (His or H); isoleucine (Ile or I); leucine (Leu or L); lysine (Lys or K); methionine (Met or M); phenylalanine (Phe or F); proline (Pro or P); serine (Ser or S); threonine (Thr or T); tryptophan (Trp or W); tyrosine (Tyr or Y); and valine (Val or V), although modified, synthetic or rare amino acids can be used if necessary. In general, amino acids can be divided into groups having a non-polar side chain (eg, Ala, Cys, Ile, Leu, Met, Phe, Pro, Val); negatively charged side chain (eg Asp, Glu); a positively charged side chain (eg Arg, His, Lys); or an uncharged polar side chain (eg, Asn, Cys, Gln, Gly, His, Met, Phe, Ser, Thr, Trp and Tyr).

Amino acid modifications include, for example, deletions from and/or insertions into, and/or substitutions of residues within the amino acid sequences of antibody constructs. Any combination of deletion, insertion and substitution is performed to obtain the final construct, provided that the final construct has the required characteristics. Amino acid changes can also alter post-translational processes of antibody constructs, such as changing the number or position of glycosylation sites.

For example, an insertion, substitution or deletion of 1, 2, 3, 4, 5 or 6 amino acids can be carried out in each of the CDRs (depending on their length, of course), while an insertion, substitution or deletion of 1 can be carried out in each of the FRs. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 25 amino acids. Preferably, amino acid sequence insertions into an antibody construct include amino/or carboxy-terminal fusions in the range of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 residues in length in polypeptides containing one hundred or more residues, as well as insertions one or more amino acid residues within a sequence. Appropriate modifications can also be made within the third domain of the antibody construct of the invention. An insertional variant of the antibody construct of the invention involves fusion of an enzyme to the N-terminus or C-terminus of the antibody construct or fusion to a polypeptide.

Residues of greatest interest for substitution mutagenesis include, but are not limited to, the heavy and/or light chain CDRs, particularly the hypervariable regions, but FR changes in the heavy and/or light chain are also contemplated. Substitutions are preferably conservative substitutions described herein. Preferably, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions can be made in CDRs, while in framework regions (FRs) substitutions can be made at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 25 amino acids, depending on the length of the CDR or FR. For example, if a CDR sequence includes 6 amino acids, it is contemplated that one, two, or three of those amino acids may be replaced. Likewise, if a CDR sequence includes 15 amino acids, it is contemplated that one, two, three, four, five or six of those amino acids may be substituted.

A useful method for identifying specific residues or regions of antibody constructs that are preferred sites for mutagenesis is called alanine scanning mutagenesis and is described in Cunningham and Wells in Science, 244: 1081-1085 (1989). Here, a residue or group of target residues within the antibody construct is identified (e.g., charged residues such as arg, asp, his, lys, and glu) and replaced with a neutral or negatively charged amino acid (most preferably alanine or polyalanine) to affect amino acid interactions with an epitope.

Those amino acid regions that exhibit functional sensitivity to substitution are then adjusted by introducing additional or different variants at or for the substitution sites. Thus, although the site or region for introducing variation in the amino acid sequence is predetermined, the nature of the mutation per se need not be predetermined. For example, to analyze or optimize the characteristics of a mutation at a given site, one can perform alanine scanning or random mutagenesis at the target codon or site and screen expressed variants of the antibody construct for the optimal combination of desired activity. Methods for performing substitution mutations in predetermined regions of DNA with a known sequence are well known, for example, mutagenesis with primer M13 and PCR mutagenesis.

- 24 043309

Screening for mutants is carried out using an antigen-binding activity assay, such as cell surface or CD3 target antigen binding.

In general, if an amino acid substitution is made in one or more or all of the heavy and/or light chain CDRs, it is preferred that the resulting substituted sequence is at least 60% or 65%, more preferably 70% or 75%, even more preferably 80% or 85% and especially preferably 90% or 95% identical to the original CDR sequence. This means that the length of the CDR determines the extent to which it is identical to the substituted sequence. For example, a CDR containing 5 amino acids is preferably 80% identical to its substituted sequence such that at least one amino acid has been replaced. Accordingly, the CDRs of an antibody construct may have varying degrees of identity to their substituted sequences, for example CDRL1 may have 80% while CDRL3 may have 90%.

Preferred substitution(s) are conservative substitutions. This means that any substitution (including a non-conservative substitution or one or more of the exemplary substitutions listed in Table 3 below) is possible, provided that the antibody construct retains its ability to bind to the target cell surface antigen through the first domain and to CD3, CD3 epsilon through the second domain, and/or its CDRs have at least 60% or 65% identity with the substituted sequence, more preferably 70% or 75%, even more preferably 80% or 85%, and particularly preferably 90 % or 95% identical to the original CDR sequence).

Conservative substitutions are given in table. 3 under the heading preferred substitutions. If such substitutions lead to a change in biological activity, then more significant changes can be made, indicated in the table. 3 as typical substitutions or additionally described below with reference to classes of amino acids, and the products are examined in relation to the required characteristic.

Table 3

Amino acid substitutions

Original Typical replacements Preferred Substitutions Ala (A) val, leu, ile val Arg(R) lys, gin, asn lys Asn(N) gin, his, asp, lys, arg gin Asp (D) glu, asn glu Cys(C) ser, ala ser Gin (Q) asn,glu asn Glu(E) asp, gin asp Gly (G) Ala ala His(H) asn, gin, lys, arg arg He(I) leu, val, met, ala, phe leu Leu (L) norleucine, ile, val, met, ala ile Lys (K) arg, gin, asn arg Met(M) leu, phe, ile leu Phe (F) leu, val, ile, ala, tyr tyr Pro (P) Ala ala Ser (S) Thr thr Thr (T) Ser ser Trp(W) tyr, phe tyr Tyr (Y) trp, phe, thr, ser phe Val(V) ile, leu, met, phe, ala leu

Significant modifications to the biological properties of the antibody construct of this invention are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone at the site of the substitution, for example, a layer of helical conformation, (b) the charge or hydrophobicity of the molecule at the target site or (c) side chain volume. Naturally occurring residues are divided into groups based on common side chain properties: (1)

- 25 043309 hydrophobic: norleucine, met, ala, val, leu, ile; (2) neutral hydrophilic: cys, ser, thr, asn, gln; (3) acidic: asp, glu; (4) basic: his, lys, arg; (5) residues that affect chain orientation: gly, pro; and (6) aromatic: trp, tyr, phe.

Non-conservative substitutions involve replacing a member of one of these classes with a member of another class. Any cysteine residue not involved in maintaining proper conformation of the antibody construct can be replaced, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant cross-linking. Conversely, cysteine linkage(s) can be added to an antibody to improve its stability (particularly when the antibody is an antibody fragment, such as an Fv fragment).

In the case of amino acid sequences, sequence identity and/or similarity is determined using standard techniques known in the art, including, but not limited to, the local sequence identity algorithm of Smith and Waterman, 1981, Adv. Appl. Math. 2:482, an alignment algorithm for determining sequence identity by Needleman and Wunsch, 1970, J. Mol. Biol. 48:443, similarity search method of Pearson and Lipman, 1988, Proc. Nat. Acad. Sci. U.S.A. 85:2444, computerized implementations of these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics software package, Genetics Computer Group, 575 Science Drive, Madison, Wis.), the Best Fit sequence program described in Devereux et al., 1984, Nucl. Acid Res. 12:387-395, preferably using default or discretionary settings. Preferably, the percent identity is calculated using FastDB based on the following parameters: mismatch penalty 1; penalty for gap 1; penalty for gap size 0.33; and compound penalty 30, Current Methods in Sequence Comparison and Analysis, Macromolecule Sequencing and Synthesis, Selected Methods and Applications, pp 127-149 (1988), Alan R. Liss, Inc.

An example of an applicable algorithm is PILEUP. PILEUP generates a multiple sequence alignment from a group of related sequences using a progressive, pairwise alignment. It can also build a tree showing the grouping relationships used to create the alignment. PILEUP uses a simplification of the progressive alignment method of Feng and Doolittle, 1987, J. Mol. Evol. 35:351-360; this method is similar to that described by Higgins and Sharp, 1989, CABIOS 5:151-153. Applicable PILEUP parameters include a default gap weight of 3.00, a default gap continuation weight of 0.10, and weighted end gaps.

Another example of an algorithm used is the BLAST algorithm, described in: Altschul et al., 1990, J. Mol. Biol. 215:403-410; Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402; and Karin et al., 1993, Proc. Natl. Acad. Sci. U.S.A. 90:5873–5787. A particularly useful BLAST program is the WU-BLAST-2 program, which was created in accordance with Altschul et al., 1996, Methods in Enzymology 266:460-480. WU-BLAST-2 uses several search parameters, most of which have default values. The adjusted parameters are set with the following values: overlap length=1, overlap fraction=0.125, threshold word length (T)=P. The HSP S and HSP S2 parameters are dynamic values and are set by the program itself, depending on the composition of the specific sequence and the composition of the specific database in which the sequence of interest is searched; however, these values can be adjusted to increase sensitivity.

An additional applicable algorithm is gap BLAST, described in Altschul et al., 1993, Nucl. Acids Res. 25:3389–3402. BLAST with gaps uses the BLOSUM-62 substitution score matrix; threshold parameter T is set to 9; the two-match method is used to initiate an extension without gaps, assigning a cost of 10+k to gaps of length k; Xu is set to 16 and Xg is set to 40 for the database search stage and 67 for the output stage of the algorithms. Alignments with gaps are initiated by an estimate corresponding to about 22 bits.

In general, the amino acid homology, similarity or identity between individual variant CDRs or VH/VL sequences is at least 60% with the sequences provided herein, and more often with preferably increasing homology or identity of at least 65 or 70 , more preferably at least 75 or 80, even more preferably at least 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and almost 100%. Similarly, the percentage (%) of nucleotide sequence identity with respect to the nucleotide sequence of the binding proteins defined herein is defined as the percentage of nucleotide residues in the candidate sequence that are identical to the nucleotide residues in the coding sequence of the antibody construct. The specific method uses the BLASTN module from WU-BLAST-2 with default parameters, with overlap length and overlap fraction set to 1 and 0.125, respectively.

In general, the homology, similarity or identity of nucleotide sequences between the nucleotide sequences encoding individual variant CDRs or VH/VL sequences and the nucleotide sequences provided herein is at least 60% and, more often, with preferably increasing homology or identity, 26 043309 component of at least 65, 70, 75, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 and almost 100%. Thus, a variant CDR or variant VH/VL region is a region with specific homology, similarity or identity to the parent CDR/VH/VL of the invention and has a biological function including, but not limited to, at least 60, 65, 70 , 75, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% specificity and/or activity of the parent CDR or VH/VL.

In one embodiment, the percentage of human germline identity of the antibody constructs of the invention is >70% or >75%, more preferably >80% or >85%, even more preferably >90%, and most preferably >91%, > 92%, >93%, >94%, >95% or even >96%. Identity with germline human antibody gene products is believed to be an important factor in reducing the risk that therapeutic proteins will induce an anti-drug immune response in the patient during treatment. Hwang & Foote (Immunogenicity of engineered antibodies; Methods 36 (2005) 3-10) demonstrated that reducing the non-human portions of drug antibody constructs resulted in a reduced risk of inducing anti-drug antibodies in patients during treatment. When comparing a sufficient number of clinically evaluated antibody drugs and corresponding immunogenicity data, there was a trend that humanization of the V regions of antibodies rendered the proteins less immunogenic (on average in 5.1% of patients) than antibodies bearing intact non-human V regions. areas (on average for 23.59% of patients). Therefore, a high degree of identity to human sequences is required for V region-based protein therapeutics in the form of antibody constructs. Alignments of VL V regions with human germline V and J segment amino acid sequences can be performed to determine germline identity (http://vbase.mrc-cpe.cam.ac.uk/) using Vector NTI software , and calculate the amino acid sequence by dividing identical amino acid residues by the total number of VL amino acid residues as a percentage. The same can be done for VH segments (http://vbase.mrc-cpe.cam.ac.uk/) except that VH CDR3 can be excluded due to the high degree of diversity and lack of alignment partners among VH CDR3 human germ line. Recombinant technologies can then be used to increase sequence identity to human germline antibody genes.

In a further embodiment, the bispecific antibody constructs of this invention demonstrate high monomer yield under standard laboratory scale conditions, for example, under a standard two-step purification process. Preferably, the monomer yield of the antibody constructs of the invention is >0.25 mg/L supernatant, more preferably >0.5 mg/L, even more preferably >1 mg/L, and most preferably >3 mg/L supernatant.

Likewise, the yield of dimeric isoforms of the antibody constructs and hence the percentage of monomers (ie monomer: (monomer+dimer)) of the antibody constructs can be determined. The productivity of monomeric and dimeric antibody constructs and the calculated percentage of monomers can, for example, be obtained from the SEC purification step of the culture supernatant from a standardized laboratory-scale production in roller bottles. In one embodiment, the percentage of monomers of the antibody constructs is >80%, more preferably >85%, even more preferably >90%, and most preferably >95%.

In one embodiment, the antibody constructs preferably have a plasma stability (ratio of EC ₅₀ with plasma to EC ₅₀ without plasma) of <5 or <4, more preferably <3.5 or <3, even more preferably <2.5 or < 2 and most preferably <1.5 or <1. Plasma stability of the antibody construct can be examined by incubating the construct in human plasma at 37°C for 24 hours followed by determination of EC ₅₀ in a chromium ⁵¹ release assay. The effector cells in the cytotoxicity assay may be stimulated enriched human CD8-positive T cells. The target cells may be, for example, CHO cells transfected with a human cell surface target antigen. The ratio between effector cells and target cells (E:M) can be selected as 10:1. The pool of human plasma used for these purposes is obtained from the blood of healthy donors collected in EDTA-coated syringes. Cellular components are removed by centrifugation and the upper plasma phase is collected and then pooled. As a control, antibody constructs were diluted immediately prior to cytotoxicity assay in RPMI-1640 medium. Plasma stability is calculated as the ratio of EC ₅₀ (after plasma incubation) to EC ₅₀ (control).

It is also preferred that the conversion of monomers to dimers of antibody constructs be low. The degree of conversion can be determined under different conditions and analyzed using high performance exclusion chromatography. For example, incubation of monomeric isoforms of const

- 27 043309 injections of antibodies can be carried out for 7 days at 37°C and concentrations of, for example, 100 μg/ml or 250 μg/ml, in an incubator. Under such conditions, it is preferred that the antibody constructs of the invention exhibit a dimer percentage of <5%, more preferably <4%, even more preferably <3%, even more preferably <2.5%, even more preferably <2%, even more preferably <1.5% and most preferably <1% or <0.5% or even 0%.

It is also preferred that the bispecific antibody constructs of the present invention exhibit low levels of dimerization after a number of freeze/thaw cycles. For example, the monomer of the antibody construct is adjusted to a concentration of 250 μg/ml, for example, in a generic formulation buffer and subjected to three freeze/thaw cycles (freezing at -80°C for 30 min followed by thawing for 30 min at room temperature) with followed by high performance SEC to determine the percentage of the initially monomeric antibody construct that has been converted to a dimeric antibody construct. Preferably, the percentage of dimers of the bispecific antibody constructs is <5%, more preferably <4%, even more preferably <3%, even more preferably <2.5%, even more preferably <2%, even more preferably <1.5%, and most preferably <1% or even <0.5%, for example after three freeze/thaw cycles.

The bispecific antibody constructs of the present invention preferably exhibit good thermal stability with an aggregation temperature >45°C or >50°C, more preferably >52°C or >54°C, even more preferably >56°C or >57°C, and most preferably >58°С or >59°С. The thermostability parameter can be defined in the context of the antibody aggregation temperature as follows. An antibody solution at a concentration of 250 μg/ml is transferred to a disposable cuvette and placed in a device for testing by dynamic light scattering (DLS). The sample is heated from 40 to 70°C at a heating rate of 0.5°C/min with constant measurement of the determined radius. The increase in radius, indicating melting and aggregation of the protein, is used to calculate the aggregation temperature of the antibody.

Alternatively, melting temperature curves can be determined by differential scanning calorimetry (DSC) to determine the characteristic biophysical protein stability of the antibody constructs. These experiments are performed using a MicroCal LLC (Northampton, MA, U.S.A) VP-DSC device. The energy absorption of the sample containing the antibody construct is recorded from 20 to 90°C and compared with the sample containing only the formulated buffer. Antibody constructs are adjusted to a final concentration of 250 μg/ml, for example, in SEC running buffer. To obtain the appropriate melting curve, the overall temperature of the sample is increased step by step. At each temperature T, the energy absorption of the sample and the standard buffer of the prepared form is recorded. The difference in energy absorption Cp (kcal/mol/°C) of the sample minus the standard is plotted as a function of the corresponding temperature. The melting point is defined as the temperature at the first maximum of energy absorption.

It is also intended that the bispecific antibody constructs to the cell surface antigen and CD3 target of the invention have a turbidity (as determined by OD340 after adjusting the concentration of the purified monomeric antibody construct to 2.5 mg/ml and incubating overnight) <0.2, preferably < 0.15, more preferably <0.12, even more preferably <0.1 and most preferably <0.08.

In a further embodiment, the antibody construct of the invention is stable at physiological pH or slightly less, i.e. pH from about 7.4 to 6.0. The better the antibody construct tolerates non-physiological pH, such as pH around 6.0, the higher the recovery rate of the antibody construct eluting from the ion exchange column relative to the total amount of protein loaded. The recovery of the antibody construct from the ion exchange (e.g., cation exchange) column at a pH of about 6.0 is preferably >30%, more preferably >40%, more preferably >50%, even more preferably >60%, even more preferably >70%, even more preferably >80%, even more preferably >90%, even more preferably >95% and most preferably >99%.

It is further intended that the bispecific antibody constructs of the present invention exhibit therapeutic efficacy or antitumor activity. This can be assessed, for example, in the study of a late-stage human tumor xenograft model described in the example below.

Those skilled in the art know how to modify or adapt certain parameters of this assay, such as the number of tumor cells injected, the injection site, the number of human T cells transplanted, the number of bispecific antibody constructs to be administered, and the schedule, while obtaining a meaningful and reproducible result. Preferably, tumor growth inhibition T/C [%] is <70 or <60, more preferably <50 or <40,

- 28 043309 even more preferably <30 or <20 and most preferably <10 or <5 or even <2.5.

In a preferred embodiment of the antibody construct of the invention, the antibody construct is a single chain antibody construct.

Also in a preferred embodiment of the antibody construct of the invention, said third domain comprises, in order from amino terminus to carboxy terminus:

hinge-CH2-CH3-linker-hinge-CH2-CH3.

In one embodiment, each of the third domain polypeptide monomers has an amino acid sequence that is at least 90% identical to a sequence selected from the group consisting of: SEQ ID NO: 17-24. In a preferred embodiment of the invention, each of these polypeptide monomers has an amino acid sequence selected from SEQ ID NO: 17-24.

Also in one embodiment of the invention, the CH2 domain of one or preferably each (both) third domain polypeptide monomers contains an intradomain cysteine disulfide bridge. As is known in the art, the term cysteine disulfide bridge refers to a functional group with the general structure R-S-S-R. This bond is also called an SS bond or a disulfide bridge and is formed by conjugating two thiol groups of cysteine residues. For the antibody construct of the invention, it is particularly preferred that the cysteines forming the cysteine disulfide bridge in the mature antibody construct are introduced into the amino acid sequence of the CH2 domain corresponding to positions 309 and 321 (Kabat numbering).

In one embodiment of the invention, the glycosylation site at position 314 of the Kabat CH2 domain is removed. Preferably, this removal of the glycosylation site is provided by the N314X substitution, where X is any amino acid except Q. The substitution is preferably the N314G substitution. In a more preferred embodiment of the invention, said CH2 domain further contains the following substitutions (positions according to Kabat): V321C and R309C (these substitutions introduce an intradomain cysteine disulfide bridge at positions 309 and 321 according to Kabat).

It is believed that the advantageous characteristics of the antibody construct of the invention compared to, for example, a hetero-Fc bispecific antibody construct known in the art (FIG. 1b) may be due to, among other things, the above-described modifications to the CH2 domain. Thus, for the construct of the invention, it is preferred that the CH2 domains in the third domain of the antibody construct of the invention contain an intradomain cysteine disulfide bridge at Kabat positions 309 and 321 and/or the glycosylation site at Kabat position 314 is removed by the N314X substitution described above, preferably replacement N314G.

In a further preferred embodiment, the CH2 domains in the third domain of the antibody construct of the invention contain an intradomain cysteine disulfide bridge at Kabat positions 309 and 321, and the glycosylation site at Kabat position 314 is removed by substitution N314G. Most preferably, the polypeptide monomer in the third domain of the antibody construct of the invention has an amino acid sequence selected from the group consisting of SEQ ID NOs: 17 and 18.

In one embodiment, the invention provides an antibody design in which:

(i) the first domain contains two antibody variable domains and the second domain contains two antibody variable domains;

(ii) the first domain contains one antibody variable domain and the second domain contains two antibody variable domains;

(iii) the first domain contains two antibody variable domains and the second domain contains one antibody variable domain; or (iv) the first domain contains one antibody variable domain and the second domain contains one antibody variable domain.

Accordingly, the first and second domains may be binding domains, each of which contains two antibody variable domains, such as VH and VL domains. Examples of such binding domains containing two antibody variable domains have been described above herein and include, for example, Fv fragments, scFv fragments or Fab fragments described above herein. Alternatively, one or both of these binding domains may contain only one variable domain. Examples of such single domain binding domains have been described above herein and include, for example, nanobodies or single variable domain antibodies containing only one variable domain, which may be VHH, VH or VL, which specifically binds an antigen or epitope independent of other V regions. or domains.

In a preferred embodiment of the antibody construct of the invention, the first and second domains are fused to the third domain via a peptide linker. A preferred peptide linker has been described above herein and is characterized by the amino acid sequence Gly-Gly-Gly-Gly-Ser, i.e. Gly ₄ Ser (SEQ ID NO: 1), or polymers thereof, i.e. (Gly ₄ Ser) _x , where x is an integer equal to 1 or more (for example, 2 or 3). A particularly preferred linker for fusing the first and second domains to the third domain is set forth in SEQ ID NO: 1.

In a preferred embodiment, the antibody construct of the invention is characterized in that it contains, in order from amino terminus to carboxy terminus:

(a) first domain;

(b) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-3;

(c) second domain;

(d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 9, 10, 11 and 12;

(e) the first polypeptide monomer of the third domain;

(f) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6, 7 and 8; and (g) a second polypeptide monomer of the third domain.

In one aspect of the invention, the target cell surface antigen bound by the first domain is a tumor antigen, an immunological disorder-specific antigen, or a viral antigen. As used herein, the term tumor antigen can be understood to refer to those antigens that are presented on tumor cells. These antigens can be presented on the cell surface with an extracellular portion, which is often found in combination with a transmembrane and cytoplasmic portion of the molecule. Sometimes these antigens can be presented only by tumor cells and never by normal cells. Tumor antigens may be expressed exclusively on tumor cells or may present a tumor-specific mutation compared to normal cells. In this case, they are called tumor-specific antigens. More common are antigens that are presented by tumor cells and normal cells and are called tumor-associated antigens. These tumor-associated antigens may be overexpressed compared to normal cells or made available for antibody binding in tumor cells due to the less compact structure of tumor tissue compared to normal tissue. As used herein, non-limiting examples of tumor antigens include CDH19, MSLN, DLL3, FLT3, EGFRvIII, CD33, CD19, CD20, and CD70.

In a preferred embodiment of the antibody construct of the invention, the tumor antigen is selected from the group consisting of CDH19, MSLN, DLL3, FLT3, EGFRvIII, CD33, CD19, CD20 and CD70.

In one aspect of the invention, the antibody construct comprises, in order from amino terminus to carboxy terminus:

(a) a first domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 52, 70, 58, 76, 88, 106, 124, 94, 112, 130, 142,160, 178, 148, 166, 184, 196, 214, 232, 202, 220, 238, 250, 266, 282, 298, 255, 271, 287, 303, 322, 338, 354, 370, 386, 402, 418, 434, 450, 466, 4 82, 498,

514, 530, 546, 327, 343, 359, 375, 391, 407, 423, 439, 455, 471, 487, 503, 519, 353, 551, 592, 608, 624, 640,

656, 672, 688, 704, 720, 736, 752, 768, 784, 800, 816, 832, 848, 864, 880, 896, 912, 928, 944, 960, 976, 992,

1008, 1024, 1040, 1056, 1072, 1088, 1104, 1120, 1136, 1152, 1168, 1184, 597, 613, 629, 645, 661, 677, 693,

709, 725, 741, 757, 773, 789, 805, 821, 837, 853, 869, 885, 901, 917, 933, 949, 965, 981, 997, 1013, 1029, 1045, 1061, 10 77, 1093, 1109, 1125, 1141, 1157, 1173, 1189, 1277, 1289, 1301, 1313, 1325, 1337, 1349, 1361, 1373, 1385, 1397, 1409, 1421, 1433, 1 445;

(b) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-3;

(c) a second domain having an amino acid sequence selected from the group consisting of SEQ ID NO: SEQ ID NO: 23, 25, 41, 43, 59, 61, 77, 79, 95, 97, 113, 115, 131, 133, 149, 151, 167, 169, 185 or 187 of WO 2008/119567 or SEQ ID NO: 15;

(d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 9, 10, 11 and 12;

(e) a first third domain polypeptide monomer having a polypeptide sequence selected from the group consisting of SEQ ID NOs: 17-24;

(f) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6, 7 and 8; and (g) a second third domain polypeptide monomer having a polypeptide sequence selected from the group consisting of SEQ ID NOs: 17-24.

In addition to this preferred embodiment, the first and second domains, which are fused via a peptide linker to a single chain polypeptide, comprise a sequence selected from the group consisting of:

- 30 043309 (a) SEQ ID NO: 53 and 59; CD33;

(b) SEQ ID NO: 71 and 77; EGFRvIII;

(c) SEQ ID NO: 89, 107, 125, 95, 113 and 131; MSLN;

(d) SEQ ID NO: 143, 161, 179, 149, 167 and 185; CDH19;

(e) SEQ ID NO: 197, 215, 233, 203, 221 and 239; DLL3;

(f) SEQ ID NO: 251, 267, 283, 299, 256, 272, 288 and 304; CD19;

(g) SEQ ID NO: 323, 339, 355, 371, 387, 403, 419, 435, 451, 467, 483, 499, 515, 531, 547, 328, 344, 360, 376, 392, 408, 424 , 440, 456, 472, 488, 504, 520, 536 and 552; FLT3;

(h) SEQ ID NO: 593, 609, 625, 641, 657, 673, 689, 705, 721, 737, 753, 769, 785, 801, 817, 833, 849, 865, 881, 897, 913, 929 , 945, 961, 977, 993, 1009, 1025, 1041, 1057, 1073, 1089, 1105, 1121, 1137, 1153, 1169, 1185, 598, 614, 630, 646, 662, 67 8, 694, 710, 726 , 742, 758, 774, 790, 806, 822, 838, 854, 870, 886, 902, 918, 934, 950, 966, 982, 998, 1014, 1030, 1046, 1062, 1078, 1094 , 1110, 1126 , 1142, 1158, 1174 and 1190; CD70;

(i) SEQ ID NO: 1268; and CD20;

(j) SEQ ID NO: 1278, 1290, 1302, 1314, 1326, 1338, 1350, 1362, 1374, 1386, 1398, 1410, 1422, 1434, 1446. CD19.

In one aspect, the antibody construct of the invention is characterized in that it has an amino acid sequence selected from the group consisting of:

(a) SEQ ID NO: 54, 55, 60 and 61; CD33;

(b) SEQ ID NO: 72, 73, 78 and 79; EGFRvIII;

(c) SEQ ID NO: 90, 91, 96, 97, 108, 109, 114 and 115; MSLN;

(d) SEQ ID NO: 144, 145, 150, 151, 162, 163, 168, 169, 180, 181, 186 and 187; CDH19;

(e) SEQ ID NO: 198, 199, 204, 205, 216, 217, 222, 223, 234, 235, 240 and 241; DLL3;

(f) SEQ ID NO: 252, 306, 257, 307, 268, 308, 273, 309, 284, 310, 289, 311, 300, 312, 305 and 313; CD19;

(g) SEQ ID NO: 324, 554, 329, 555, 340, 556, 345, 557, 356, 558, 361, 559, 372, 560, 377, 561, 388, 562, 393, 563, 404, 564 , 409, 565, 420, 566, 425, 567, 436, 568, 441, 569, 452, 570, 457, 571, 468, 572, 473, 573, 484, 574, 489, 575, 500, 576, 505 , 577, 516, 578, 521, 579, 532, 580, 537, 581, 548, 582, 553 and 583; FLT3;

(h) SEQ ID NO: 594, 610, 626, 642, 658, 674, 690, 706, 722, 738, 754, 77, 786, 802, 818, 834, 850, 866, 882, 898, 914, 930 , 946, 962, 978, 994, 1010, 1026, 1042, 1058, 1074, 1090, 1106, 1122, 1138, 1154, 1170, 1186, 599, 615, 631, 647, 663, 67 9, 695, 711, 727 , 743, 759, 775, 791, 807, 823, 839, 855, 871, 887, 903, 919, 935, 951, 967, 983, 999, 1015, 1031, 1047, 1063, 1079, 1095 , 1111, 1127 , 1143, 1159, 1175, 1191 and 1192-1267; CD70;

(i) SEQ ID NO: 43; CD20;

(j) SEQ ID NO: 1279, 1280, 1291, 1292, 1303, 1304, 1315, 1316, 1327, 1328, 1339, 1340, 1351, 1352, 1363, 1364, 1375, 1376, 1387, 1388, 1399,1400 , 1411, 1412, 1423, 1424, 1435, 1436, 1447, 1448. CD19.

The invention further provides a polynucleotide/nucleic acid molecule encoding an antibody construct of the invention. A polynucleotide is a biopolymer consisting of 13 or more nucleotide monomers covalently linked in a chain. DNA (such as cDNA) and RNA (such as mRNA) are examples of polynucleotides with different biological functions. Nucleotides are organic molecules that serve as monomers or subunits of nucleic acid molecules such as DNA or RNA. A nucleic acid molecule or polynucleotide can be double-stranded or single-stranded, linear or circular. Preferably it is in a vector, which is preferably in a host cell. Said host cell, for example, after transformation or transfection with a vector or polynucleotide according to the invention, is capable of expressing an antibody construct. For this purpose, the polynucleotide or nucleic acid molecule is operably linked to regulatory sequences.

The genetic code is a set of rules by which information encoded in genetic material (nucleic acids) is translated into protein. Biological transcription in living cells is carried out by the ribosome, which binds amino acids in the order specified by the mRNA, using tRNA molecules to carry the amino acids and to read trinucleotides of the mRNA at a time. The code specifies how the sequences of these nucleotide triplets, called codons, determine which amino acid should be added next during protein synthesis. With some exceptions, a trinucleotide codon in a nucleic acid sequence specifies one amino acid. Since the vast majority of genes are encoded by exactly the same code, this particular code is often called the canonical or standard genetic code. Although the genetic code determines the protein sequence for a given coding region, other genomic regions can influence when and where these proteins are made.

In addition, the invention provides a vector containing a polynucleotide/nucleic acid molecule according to the invention. A vector is a nucleic acid molecule used as a carrier to transfer (foreign) genetic material into a cell. The term vector includes, but is not limited to, plasmids, viruses, cosmids and artificial chromosomes. In general, the constructed vectors contain an origin of replication, a multicloning site, and a selectable marker. The vector itself is generally a nucleotide sequence

- 31 043309 activity, usually a DNA sequence that contains an insert (transgene), and a larger sequence that serves as the backbone of the vector. Modern vectors may include additional elements beyond the transgene insert and backbone: promoter, genetic marker, antibiotic resistance, reporter gene, targeting sequence, protein purification tag. Vectors, called expression vectors (expression constructs), are specifically designed to express a transgene in a target cell and generally contain regulatory sequences.

The term regulatory sequences refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. Regulatory sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence and a ribosome binding site. Promoters, polyadenylation signals, and enhancers are known to be used in eukaryotic cells.

A nucleic acid is operably linked when it is in a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader sequence is operably linked to DNA for a polypeptide if it is expressed as a precursor protein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects transcription of the sequence; or the ribosome binding site is operably linked to the coding sequence if it is positioned to facilitate translation. In general, operably linked means that the linked DNA sequences are contiguous and, in the case of a secretory leader sequence, contiguous in reading phase. In this case, enhancers should not be adjacent. Binding is accomplished by ligation at convenient restriction sites. If such regions do not exist, synthetic adapters or linkers are used in accordance with traditional practice.

Transfection is the process of deliberately introducing nucleic acid molecules or polynucleotides (including vectors) into target cells. The term is used primarily for non-viral methods in eukaryotic cells. Transduction is often used to describe the virus-mediated transfer of nucleic acid molecules or polynucleotides. Transfection of animal cells typically involves opening temporary pores or holes in the cell membrane to allow uptake of material. Transfection can be done using calcium phosphate, by electroporation, by cell compression, or by mixing a cationic lipid with the material to produce liposomes, which fuse with the cell membrane and leave their cargo inside.

The term transformation is used to describe the non-viral transfer of nucleic acid molecules or polynucleotides (including vectors) into bacteria and also into non-animal eukaryotic cells, including plant cells. Transformation, therefore, is a genetic change in a bacterial or non-animal eukaryotic cell resulting from direct absorption through the cell membrane(s) from the environment and subsequent incorporation of exogenous genetic material (nucleic acid molecules). Transformation can be carried out by artificial means. For transformation to occur, the cells or bacteria must be in a state of competence, which can occur as a time-limited response to external conditions such as starvation and cell density.

In addition, the invention provides a host cell transformed or transfected with a polynucleotide/nucleic acid molecule or vector according to the invention. As used herein, the terms host cell or recipient cell are intended to include any individual cell or culture of cells that can be or have been recipients of vectors, exogenous nucleic acid molecules and polynucleotides encoding an antibody construct of the present invention; and/or recipients of the antibody construct itself. The introduction of the corresponding material into the cell is carried out by transformation, transfection, etc. The term host cell is also intended to include the progeny or potential progeny of a single cell. Since certain modifications may occur in subsequent generations due to natural, accidental or intentional mutation or due to environmental influences, such offspring may not actually be completely identical (in morphology or in the set of genomic or total DNA) with the parent cell, but all is equally, in the context of this document, included within the scope of the specified term. Suitable host cells include prokaryotic or eukaryotic cells and also include, but are not limited to, bacteria, yeast cells, fungal cells, plant cells and animal cells, such as insect cells and mammalian cells, such as mice, rats, macaques or humans.

The antibody construct of the invention can be produced in bacteria. After expression, the antibody construct of the invention is isolated from the E. coli cell paste into a soluble fraction and can then be purified using, for example, affinity or size exclusion chromatography. The final purification can be carried out in a similar manner to the purification process for an antibody expressed by e.g.

- 32 043309 in CHO cells.

In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable hosts for cloning or expressing the antibody construct of the invention. Saccharomyces cerevisiae or common baker's yeast is the most commonly used microbial host of lower eukaryotes. However, a large number of other genera, species and strains are generally accepted and applicable in this case, for example, Schizosaccharomyces pombe, hosts from Kluyveromyces, such as K. lactis, K. fragilis (ATCC 12424), K. bulgaricus (ATCC 16045), K A. wickeramii (ATCC 24178), K. waltii (ATCC 56500), K. drosophilarum (ATCC 36906), K. thermotolerans and K. marxianus; yarrowia (EP 402 226); Pichia pastoris (EP 183 070); Candida; Trichoderma reesia (EP 244 234); Neurospora crassa; Schwanniomyces such as Schwanniomyces occidentalis; and filamentous fungi such as Neurospora, Penicillium, Tolypocladium, and Aspergillus hosts such as A. nidulans and A. niger.

Suitable host cells for expressing the glycosylated antibody construct of the invention are derived from multicellular organisms. Examples of invertebrate cells include plant and insect cells. Numerous baculovirus strains and variants and corresponding permissive insect host cells have been identified, such as Spodoptera frugiperda (caterpillar), Aedes aegypti (sandfly), Aedes albopictus (sandfly), Drosophila melanogaster (fruit fly) and Bombyx mori. Various viral strains for transfection are publicly available, for example Autographa californica NPV variant L-1 and Bombyx mori NPV strain Bm-5, and such viruses can be used as the virus of the present invention, in particular for transfecting Spodoptera frugiperda cells.

Plant cell cultures of cotton, corn, potato, soybean, petunia, tomato, Arabidopsis and tobacco can also be used as hosts. Cloning and expression vectors used to produce proteins in plant cell culture are known to those skilled in the art. See, for example, Hiatt et al., Nature (1989) 342: 76-78, Owen et al. (1992) Bio/Technology 10: 790-794, Artsaenko et al. (1995) The Plant J 8: 745-750, and Fecker et al. (1996) Plant Mol Biol 32: 979–986.

However, vertebrate cells are of greatest interest, and propagation of vertebrate cells in culture (tissue culture) has become a routine procedure. Examples of useful mammalian host cell lines include the SV40 transformed monkey kidney line CV1 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol. 36: 59 (1977)); newborn hamster kidney cells (BHK, ATCC CCL 10); Chinese hamster ovary/-DHFR cells (CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA 77: 4216 (1980)); Mouse Sertoli cells (TM4, Mather, Biol. Reprod. 23: 243-251 (1980)); monkey kidney cells (CVI ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); gray rat liver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2.1413 8065); mouse mammary tumor cells (MMT 060562, ATCC CCL5 1); TRI cells (Mather et al., Annals N. Y Acad. Sci. (1982) 383: 44-68); MRC 5 cells; FS4 cells; and the human hepatoma line (Hep G2).

In a further embodiment, the invention provides a process for producing an antibody construct of the invention, comprising culturing a host cell of the invention under conditions allowing expression of the antibody construct of the invention and isolating the resulting antibody construct from the culture.

As used herein, the term culture refers to the in vitro maintenance, differentiation, growth, proliferation and/or propagation of cells under suitable environmental conditions. The term expression includes any step carried out to produce the antibody construct of the invention, including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification and secretion.

When using recombinant technologies, the antibody construct can be produced inside the cell, in the periplasmic space, or it can be directly secreted into the medium. If the antibody construct is produced intracellularly, the first step is to remove particulate debris, both host cells and lysed fragments, for example by centrifugation or ultrafiltration. Carter et al., Bio/Technology 10: 163-167 (1992) describes a procedure for isolating antibodies that are secreted into the periplasmic space of E. coli. Briefly, the cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA and phenylmethylsulfonyl fluoride (PMSF) for about 30 min. Cellular debris is removed by centrifugation. If the antibody is secreted into the medium, supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, such as an Amicon or Millipore Pellicon ultrafiltration unit. At any of the above steps, a protease inhibitor such as PMSF may be included to inhibit proteolysis, and antibiotics may be included to prevent the growth of introduced contaminants.

The antibody construct of the invention obtained from host cells can be isolated or

- 33 043309 purify using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis and affinity chromatography. Also, depending on the antibody intended for isolation, other protein purification techniques are available, such as ion exchange column fractionation, ethanol precipitation, reverse phase HPLC, silica gel chromatography, heparine sepharose™ chromatography, chromatography on an anion or cation exchange resin (such as polyaspartic acid column), chromatofocusing, SDS-PAGE and ammonium sulfate precipitation. If the antibody construct of the invention contains a CH3 domain, Bakerbond ABX resin (J.T. Baker, Phillipsburg, NJ) is used for purification.

Affinity chromatography is the preferred purification technique. The matrix to which the affinity ligand is attached is most often agarose, but other matrices are also available. Mechanically stable matrices such as controlled pore glass or poly(styrene divinyl)benzene provide higher flow rates and shorter processing times compared to agarose.

In addition, the invention provides a pharmaceutical composition containing an antibody construct according to the invention or an antibody construct obtained in accordance with the method according to the invention. For the pharmaceutical composition of the invention, it is preferred that the antibody construct homogeneity is >80%, more preferably >81%, >82%, >83%, >84% or >85%, even more preferably >86%, >87%, >88 %, >89% or >90%, even more preferably >91%, >92%, >93%, >94% or >95% and most preferably >96%, >97%, >98% or >99%.

As used herein, the term pharmaceutical composition refers to a composition suitable for administration to a patient, preferably a human patient. A particularly preferred pharmaceutical composition according to the present invention contains one or more antibody constructs according to the invention, preferably in a therapeutically effective amount. Preferably, the pharmaceutical composition further contains suitable formulated forms of one or more (pharmaceutically effective) carriers, stabilizers, excipients, diluents, solubilizers, surfactants, emulsifiers, preservatives and/or adjuvants. Suitable composition constituents are preferably non-toxic to recipients at the dosages and concentrations used. Pharmaceutical compositions according to the invention include, but are not limited to, liquid, frozen and lyophilized compositions.

The compositions of the invention may contain a pharmaceutically acceptable carrier. Generally, as used herein, a pharmaceutically acceptable carrier means any and all aqueous and non-aqueous solutions, sterile solutions, solvents, buffers, such as phosphate-buffered saline (PBS), water, suspensions, emulsions, such as oil/water emulsions, various types of wetting agents, liposomes, dispersion media and coatings that are compatible with pharmaceutical administration, in particular parenteral administration. The use of such vehicles and agents in pharmaceutical compositions is well known in the art, and compositions containing such carriers can be formulated by well known conventional methods.

In certain embodiments, the invention provides pharmaceutical compositions comprising an antibody construct of the invention and additionally one or more excipients, such as those described for illustrative purposes in this section and elsewhere herein. In this regard, excipients can be used in the invention for many purposes, such as adjusting the physical, chemical or biological properties of the formulations, for example, adjusting the viscosity, and/or processes according to the invention to improve the effectiveness and/or to stabilize such formulations and processes against degradation and deterioration due, for example, to stresses that occur during production, transport, storage, preparation before use, administration and afterwards.

In certain embodiments of the invention, the pharmaceutical composition may contain constituent materials for the purpose of modifying, maintaining or maintaining, for example, pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, absorption or penetration of the composition (see REMINGTON'S PHARMACEUTICAL SCIENCES, 18'' Edition, (A.R. Genrmo, ed.), 1990, Mack Publishing Company). In such embodiments, suitable constituent materials may include, but are not limited to:

amino acids such as glycine, alanine, glutamine, asparagine, threonine, proline, 2-phenylalanine, including charged amino acids, preferably lysine, lysine acetate, arginine, glutamate and/or histidine;

antimicrobials such as antibacterial and antifungal agents;

antioxidants such as ascorbic acid, methionine, sodium sulfite or sodium hydrogensulfite;

- 34 043309 buffers, buffer systems or buffering agents that are used to maintain the composition at physiological pH or slightly lower pH; examples of buffers are borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids, succinate, phosphate and histidine; for example, Tris buffer with a pH of about 7.0-8.5;

non-aqueous solvents such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate;

aqueous vehicles, including water, alcohol-water vehicles, emulsions or suspensions, including saline and buffered media;

biodegradable polymers such as polyesters;

bulking agents such as mannitol or glycine;

chelating agents such as ethylenediaminetetraacetic acid (EDTA);

isotonic agents and agents that delay absorption;

complexing agents such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin;

fillers;

monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); the carbohydrates may be non-reducing sugars, preferably trehalose, sucrose, octasulfate, sorbitol or xylitol;

(low molecular weight) proteins, polypeptides or protein carriers such as human or bovine serum albumin, gelatin or immunoglobulins, preferably of human origin;

dyes and flavors;

sulfur-containing reducing agents such as glutathione, thioctic acid, sodium thioglycolate, thioglycerol, [alpha]-monothioglycerol and sodium thiosulfate;

thinners;

emulsifiers;

hydrophilic polymers such as polyvinylpyrrolidone;

salt-forming counterions such as sodium;

preservatives such as antimicrobial agents, antioxidants, chelating agents, inert gases and the like; examples are benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide;

metal complexes such as Zn-protein complexes;

solvents and co-solvents (such as glycerin, propylene glycol or polyethylene glycol);

sugars and sugar alcohols such as trehalose, sucrose, octasulfate, mannitol, sorbitol or xylitol, stachyose, mannose, sorbose, xylose, ribose, myoinisitose, galactose, lactitol, ribitol, myoinositol, galactitol, glycerol, cyclitols (eg inositol), polyethylene glycol; and polyhydric sugar alcohols;

suspending agents;

surfactants or wetting agents such as pluronics, PEGs, sorbitan esters, polysorbates such as polysorbate 20, polysorbate, triton, tromethamine, lecithin, cholesterol, tyloxapal; the surfactants may be detergents, preferably with a molecular weight >1.2 kDa, and/or a polyester, preferably with a molecular weight >3 kDa; non-limiting examples of preferred detergents include Tween 20, Tween 40, Tween 60, Tween 80 and Tween 85; non-limiting examples of preferred polyesters include PEG 3000, PEG 3350, PEG 4000 and PEG 5000;

stability enhancing agents such as sucrose or sorbitol;

tonicity agents such as alkali metal halides, preferably sodium or potassium chloride, mannitol, sorbitol;

parenteral delivery agents including sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fatty oils;

intravenous delivery agents, including fluid and nutrient replenishers, electrolyte replenishers (eg, Ringer's dextrose).

It will be apparent to those skilled in the art that different constituents of a pharmaceutical composition (eg, those listed above) may have different effects, for example, an amino acid may act as a buffer, stabilizer and/or antioxidant; mannitol may act as a bulking agent and/or a tonicity agent; sodium chloride may act as a delivery agent and/or a tonicity agent.

It is understood that the composition of the invention may contain, in addition to the polypeptide of the invention as defined herein, additional biologically active agents, depending on the intended use of the composition. Such agents may be drugs that act on the gastrointestinal system, cytostatic drugs, drugs that prevent hyperuricemia, drugs that inhibit immunoreactions (for example, corticosteroids), drugs that modulate the inflammatory response, drugs that acting on the circulatory system, and/or agents such as cytokines known in the art. It is also intended that the antibody construct of this invention be used in co-therapy, i.e. in combination with another anticancer drug.

In certain embodiments, the optimal pharmaceutical composition is determined by one skilled in the art depending, for example, on the intended route of administration, delivery format, and dosage required. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, above. In certain embodiments, such compositions may affect the physical state, stability, in vivo release rate, and in vivo clearance rate of the antibody construct of the invention. In certain embodiments of the invention, the basic base solution or carrier in the pharmaceutical composition may be either aqueous or non-aqueous in nature. For example, a suitable base solution or carrier may be water for injection, physiological saline or artificial cerebrospinal fluid, possibly supplemented with other materials customary in compositions for parenteral administration. Additional typical stock solutions are neutral buffered saline or saline mixed with serum albumin. In certain embodiments, the antibody construct compositions of the invention can be prepared for storage by mixing the selected composition, having the desired degree of purity, with the optimal constituent agents (REMINGTON'S PHARMACEUTICAL SCIENCES, supra) in the form of a lyophilized lozenge or an aqueous solution. Additionally, in certain embodiments, the antibody construct of the invention can be formulated as a lyophilisate using appropriate excipients, such as sucrose.

If parenteral administration is contemplated, therapeutic compositions for use in this invention can be prepared in the form of a pyrogen-free, parenterally acceptable aqueous solution containing the desired antibody construct of the invention in a pharmaceutically acceptable stock solution. A particularly suitable stock solution for parenteral injection is sterile distilled water, in which the antibody construct of the invention is prepared in a sterile, isotonic solution that is properly preserved. In certain embodiments, the formulation may include a formulated formulation of the desired molecule with an agent, such as injectable microspheres, biodegradable particles, polymeric compounds (such as polylactic acid or polyglycolic acid), granules, or liposomes, which may provide controlled or sustained release of the product that may delivered by depot injection. In certain embodiments of the invention, hyaluronic acid can also be used, the effect of which is to promote prolonged circulation. In certain embodiments of the invention, implantable devices can be used to introduce the desired antibody construct.

Additional pharmaceutical compositions will be apparent to those skilled in the art, including formulations containing the antibody construct of the invention in sustained release or controlled delivery/release formulations. Techniques for the preparation of various other agents for delayed or controlled delivery, such as liposomal carriers, biodegradable microparticles or porous granules and depot injections, are also known to those skilled in the art. See, for example, International Patent Application No. PCT/US93/00829, which describes the controlled release of porous polymer microparticles for the delivery of pharmaceutical compositions. Sustained release formulations may contain semi-permeable polymer matrices in the form of molded articles, such as films or microcapsules. Sustained release matrices may contain polyesters, hydrogels, polylactides (described in US Patent No. 3,773,919 and European Patent Application Publication No. EP 058481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., 1983, Biopolymers 2:547-556), poly(2-hydroxyethyl methacrylate) (Langer et al., 1981, J. Biomed. Mater. Res. 15:167277 and Langer, 1982, Chem. Tech. 12:98-105) , ethylene vinyl acetate (Langer et al., 1981, supra) or poly-O(-)3-hydroxybutyric acid (European Patent Application Publication No. EP 133988). Sustained release compositions may also contain liposomes, which can be prepared by any of several methods known in the art. See, for example, Eppstein et al., 1985, Proc. Natl. Acad. Sci. U.S.A. 82:3688-3692; publication of European patent applications No. EP 036676; EP 088046 and EP 143949.

The antibody construct can also be contained in microcapsules prepared, for example, by coacervation or interfacial polymerization methods (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are described in Remington's Pharmaceutical Sciences, 16th edition, Oslo, A., Ed., (1980).

- 36 043309

Pharmaceutical compositions used for in vivo administration are generally provided in the form of sterile preparations. Sterilization can be accomplished by filtration through sterile filter membranes. If the composition is lyophilized, sterilization using this method can be carried out before or after lyophilization and reconstitution. Compositions for parenteral administration can be stored in lyophilized form or in solution. Parenteral compositions are generally placed in a container having a sterile entry port, such as an intravenous solution bag or vial having a stopper pierced by a hypodermic injection needle.

Another aspect of the invention includes self-buffering formulations of the antibody construct of the invention that can be used as pharmaceutical compositions, as described in international patent application WO 06138181A2 (PCT/US2006/022599). Various descriptions are available for the stabilization of proteins and constituent materials, as well as methods used in connection therewith, for example, Arakawa et al., Solvent interactions in pharmaceutical formulations, Pharm Res. 8(3): 285-91 (1991); Kendrick et al., Physical stabilization of proteins in aqueous solutions in: RATIONAL DESIGN OF STABLE PROTEIN FORMULATIONS: THEORY AND PRACTICE, Carpenter and Manning, eds. Pharmaceutical Biotechnology. 13: 61-84 (2002), and Randolph et al., Surfactant-protein interactions, Pharm Biotechnol. 13: 159-75 (2002), see in particular the parts relating to excipients and associated processes for self-buffering protein formulations in accordance with this invention, in particular protein pharmaceutical products and processes for veterinary and/or veterinary applications human medicine.

In accordance with some embodiments of the invention, salts can be used, for example, to adjust the ionic strength and/or isotonicity of the formulation, and/or to improve the solubility and/or physical stability of the protein or other ingredient of the composition in accordance with the invention. As is well known, ions can stabilize the native state of proteins by binding to charged residues on the surface of the protein and by shielding charged and polar groups in the protein and reducing the strength of their electrostatic, attractive and repulsive interactions. Ions can also stabilize the denatured state of a protein by binding, in particular, to the denatured peptide bonds (--CONH) of the protein. In addition, ionic interaction with charged and polar groups in a protein can reduce intermolecular electrostatic interactions and thus prevent or reduce protein aggregation and insolubility.

Ionic molecules differ significantly in their effect on proteins. A large number of categorical classifications of ions and their effects on proteins have been developed that can be used in the preparation of pharmaceutical compositions in accordance with the invention. One example is the Hoffmeister series, in which ionic and polar nonionic solutes are ordered according to their effect on the conformational stability of proteins in solution. Stabilizing solutes are called kosmotropic. Destabilizing solutes are called chaotropic. Cosmotropes are typically used in high concentrations (eg, >1 molar ammonium sulfate) to precipitate proteins from solution (salting out). Chaotropes are typically used to denature and/or solubilize proteins (salting-in). The relative effectiveness of ions in salting in and salting out determines their position in the Hofmeister series.

Free amino acids can be used in formulated antibody constructs of the invention in accordance with various embodiments of the invention as bulking agents, stabilizers and antioxidants, as well as for other standard uses. Lysine, proline, serine and alanine can be used to stabilize proteins in their finished form. Glycine is used during lyophilization to ensure the correct structure and properties of the cake. Arginine can be used to inhibit protein aggregation, in both liquid and lyophilized formulations. Methionine is used as an antioxidant.

Polyols include sugars, such as mannitol, sucrose and sorbitol, as well as polyhydric alcohols, such as, for example, glycerol and propylene glycol, and, for purposes of discussion herein, polyethylene glycol (PEG) and related substances. Polyols are kosmotropic. They are useful stabilizing agents in both liquid and lyophilized formulations to protect proteins from processes of physical and chemical degradation. Polyols are also used to adjust the tonicity of finished forms. Among the polyols used in selected embodiments of the invention is mannitol, which is typically used to ensure structural stability of the lozenge in lyophilized formulations. It guarantees the structural stability of the cake. In general, it is used with a lyoprotectant, such as sucrose. Sorbitol and sucrose are among the preferred agents for adjusting tonicity and for use as stabilizers to protect against freeze-thaw stress during transportation or bulk preparation during the manufacturing process. Reducing sugars (which contain free aldehyde or ketone groups), such as glucose or lactose, can glycate surface

- 37 043309 lysine and arginine residues. Therefore, in general they are not among the preferred polyols for use in accordance with this invention. In addition, sugars that form reactive molecules, such as sucrose, which hydrolyzes to fructose and glucose under acidic conditions and subsequently leads to glycation, are therefore also not among the preferred polyols according to the invention. PEG is used to stabilize proteins and as a cryoprotectant, and therefore can be used in this invention.

Embodiments of the antibody design of the invention further include surfactants. Protein molecules can be susceptible to adsorption to surfaces and denaturation and subsequent aggregation at air-liquid, solid-liquid, and liquid-liquid interfaces. These effects are generally inversely proportional to protein concentration. These harmful interactions are generally inversely proportional to protein concentration and are typically aggravated by physical agitation such as occurs during shipping and handling of the product. Surfactants are typically used to prevent, minimize or reduce surface adsorption. In this regard, useful surfactants according to the invention include polysorbate 20, polysorbate 80, other fatty acid esters of sorbitan polyethoxylates and poloxamer 188. Surfactants are also commonly used to control the conformational stability of a protein. The use of surfactants in this regard is protein specific, since any given surfactant will stabilize some proteins and destabilize others.

Polysorbates are sensitive to oxidative degradation and often, as supplied, contain sufficient amounts of peroxides to cause oxidation of protein side chains, particularly methionine. Therefore, polysorbates should be used cautiously and, when used, should be used at the lowest effective concentration. In this regard, polysorbates are an example of the general rule that excipients should be used at the lowest effective concentration.

Embodiments of the antibody constructs of the invention further include the use of one or more antioxidants. Harmful oxidation of proteins in pharmaceutical finished forms can be prevented to some extent by maintaining proper external oxygen levels and temperature and avoiding exposure to light. Antioxidant excipients can also be used to prevent oxidative degradation of proteins. Among the antioxidants useful in this regard are reducing agents, oxygen/free radical scavengers and chelating agents. Antioxidants for use in the therapeutic protein formulations of the invention are preferably water soluble and remain active throughout the shelf life of the product. EDTA is the preferred antioxidant in this regard according to the invention. Antioxidants can damage proteins. For example, reducing agents, such as glutathione in particular, can break intramolecular disulfide bonds. Thus, antioxidants for use in the invention are selected to, among other things, eliminate or substantially reduce the potential for them to damage proteins in the formulated form.

The prepared forms in accordance with the invention may contain metal ions that are cofactors of proteins and are necessary for the formation of protein coordination complexes, for example, like zinc, which is necessary for the formation of some insulin suspensions. Metal ions can also inhibit certain processes that break down proteins. However, metal ions can also catalyze physical and chemical processes that break down proteins. Magnesium ions (10-120 mM) can be used to inhibit the isomerization of aspartic acid to isoaspartic acid. Ca ⁺² ions (up to 100 mM) can increase the stability of human deoxyribonuclease. However, Mg ⁺² , Mn ⁺² and Zn ⁺² can destabilize recombinant human DNase. Similarly, Ca ⁺² and Sr ⁺² can stabilize factor VIII, while it can be destabilized by Mg ⁺² , Mn ⁺² and Zn ⁺² , Cu ⁺² and Fe ⁺² , and its aggregation can be increased by Al ⁺³ ions.

Embodiments of the finished forms of the antibody construct of the invention further include the use of one or more preservatives. Preservatives are necessary when developing multi-dose parenteral formulations that require more than one set from the same container. Their main function is to inhibit the growth of microorganisms and guarantee the sterility of the product throughout the shelf life or period of use of the medicinal product. Commonly used preservatives include benzyl alcohol, phenol and m-cresol. Although preservatives have long been used with small molecule parenterals, developing protein formulations that contain preservatives can be challenging. Preservatives almost always have a destabilizing effect (aggregation) on proteins, and this has been a major factor in limiting their use in multi-dose protein formulations. Currently, most protein drugs are formulated for one use only. However, when multi-dose formulations are available, they have the added benefit of providing patient convenience and increasing market competitiveness. A good example is related to the human mountain

- 38 043309 growth monom (hGH), when the development of preservative-containing finished forms led to the commercialization of more convenient, reusable pen syringes. Today, at least four such pen devices containing preformed forms of hGH with preservatives are available on the market. Norditropin (liquid, Novo Nordisk), Nutropin AQ (liquid, Genentech), and genotropin (lyophilized, dual-chamber cartridge, Pharmacia & Upjohn) contain phenol, while Somatrope (Eli Lilly) is formulated with m-cresol. Several aspects must be considered when preparing and developing preservative-containing dosage forms. The effective concentration of the preservative in the drug product must be optimized. This requires testing a given preservative in a dosage form in a concentration range that provides antimicrobial effectiveness without compromising protein stability.

As can be expected, the development of liquid formulations containing preservatives is more complex than in the case of lyophilized formulations. Freeze-dried products can be lyophilized without preservative and reconstituted with a preservative-containing diluent at the time of use. This reduces the time the preservative is in contact with the protein, thereby significantly minimizing the associated stability risk. In the case of liquid formulations, the effectiveness and stability of the preservative should be maintained throughout the shelf life of the product (about 18 to 24 months). An important point to note is that the effectiveness of the preservative must be manifested in the final finished form containing the active drug and all auxiliary components.

The antibody constructs described herein can also be prepared as immunoliposomes. A liposome is a small vesicle composed of various types of lipids, phospholipids and/or surfactants that is used to deliver a drug into the body of mammals. Liposome components typically have a bilayer arrangement, similar to the lipid ordering of biological membranes. Liposomes containing the antibody construct are prepared by methods known in the art, such as those described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980); US patents No. 4485045 and 4544545; and WO 97/38731. Liposomes with extended circulation time are described in US Pat. No. 5,013,556. Particularly useful liposomes can be created by reverse phase evaporation with a lipid composition containing phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are passed through filters with a certain pore size to obtain liposomes with the required diameter. Fab' fragments of the antibody construct of the present invention can be conjugated to liposomes as described in Martin et al. J Biol. Chem. 257: 286-288 (1982), via a disulfide exchange reaction. The liposome optionally contains a chemotherapeutic agent. See Gabizon et al. J. National Cancer Inst. 81 (19) 1484 (1989).

Once the pharmaceutical composition is prepared, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, crystal, or as a dehydrated or lyophilized powder. Such formulations may be stored in a ready-to-use form or in a form (eg, lyophilized) that is reconstituted before administration.

The biological activity of the pharmaceutical composition defined herein can be determined, for example, using a cytotoxicity assay as described in the examples below, in WO 99/54440 or in Schlereth et al. (Cancer Immunol. Immunother. 20 (2005), 1-12). As used herein, efficacy or in vivo efficacy refers to the response to therapy with a pharmaceutical composition of the invention as assessed by standardized NCI (National Cancer Institute) response criteria. The success or in vivo effectiveness of a therapy using a pharmaceutical composition according to the invention relates to the effectiveness of the composition in relation to its intended purpose, i.e. the ability of the composition to have the desired effect, i.e. destruction of pathological cells, such as tumor cells. In vivo efficacy can be monitored using generally accepted standard methods for appropriate disease entities, including, but not limited to, white blood cell count, leukocyte count, fluorescent activated cell sorting, and bone marrow aspiration. In addition, various disease-specific clinical chemistry parameters and other generally accepted standard methods can be used. In addition, computed tomography, x-ray, nuclear magnetic resonance imaging (eg, to assess response based on National Cancer Institute criteria) can be used [Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP: Presentation at an international workshop on standardized response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group J Clin Oncol 1999 Apr;17(4):1244]), positron emission tomography scan, white blood cell count, leukocyte count, fluorescence activated cell sorting, bone marrow aspiration, biopsy/histology lymph nodes and various lymphoma-specific clinical chemistry parameters (eg, lactate dehydrogenase levels) and others

- 39 043309 generally accepted standard methods.

Another major challenge in the development of medicinal products, such as the pharmaceutical composition of the invention, is predictable modulation of pharmacokinetic properties. For this purpose, the pharmacokinetic profile of the drug candidate can be established, i.e. a profile of pharmacokinetic parameters that influence the ability of a particular drug to treat a given pathological condition. Pharmacokinetic parameters of a drug that influence the drug's ability to treat a particular entity include, but are not limited to: half-life, volume of distribution, first pass metabolism in the liver, and degree of serum binding. The effectiveness of a given drug agent can be influenced by each of the above parameters. An implied characteristic of antibody constructs of the present invention provided with a specific FC modality is that they entail, for example, a difference in pharmacokinetic behavior. The extended half-life antibody targeting construct of the present invention preferably exhibits an unexpectedly increased in vivo retention time compared to canonical non-HLE versions of the antibody construct.

Half-life means the time during which 50% of the administered drug is eliminated through biological processes such as metabolism, excretion, etc. First-pass metabolism in the liver refers to the susceptibility of a drug to metabolism after first contact with the liver, i.e. during the first passage through the liver. The volume of distribution means the extent to which a drug is retained in various compartments of the body, such as, for example, intracellular and extracellular spaces, tissues or organs, etc., and the distribution of the drug in these compartments. Serum binding refers to the susceptibility of a drug to interact with and bind to serum proteins such as albumin, resulting in reduced or lost biological activity of the drug.

Pharmacokinetic parameters also include bioavailability, time lag (Tlag), Tmax, rate of absorption, onset of action and/or Cmax for a given amount of drug administered. Bioavailability refers to the amount of drug in the blood compartment. Time lag refers to the lag time between the administration of a drug and its detection and detection in blood or plasma. Tmax represents the time at which the maximum blood concentration of a drug is reached, and Cmax represents the maximum blood concentration obtained with a given drug. The time required to achieve the drug concentration in the blood or tissue required for biological action is influenced by all parameters.

Pharmacokinetic parameters of bispecific antibody constructs demonstrating cross-species specificity that can be determined in preclinical animal studies in non-chimpanzee primates as noted above are also reported, for example, in Schlereth et al. (Cancer Immunol. Immunother. 20 (2005), 1-12).

In a preferred aspect of the invention, the pharmaceutical composition is stable for at least four weeks at about -20°C. As is evident from the accompanying examples, the quality of the antibody construct of the invention compared to the quality of prior art antibody constructs can be examined using different systems. It is understood that these studies are consistent with the ICH Harmonized Tripartite Guideline: Stability Testing of Biotechnological/Biological Products Q5C and Specifications: Test procedures and Acceptance Criteria for Biotech Biotechnological/Biological Products Q6B and are therefore selected to provide a stability-indicative profile that provides confidence in detecting changes in product identity, purity and potency. It is generally accepted that the term purity is a relative term. Due to the effects of glycosylation, deamidation, or other heterogeneity, the absolute purity of a biotechnological/biological product typically must be assessed by more than one method, and the resulting purity value depends on the method. For stability testing purposes, purity studies should focus on methods for determining degradation products.

To assess the quality of a pharmaceutical composition containing an antibody construct according to the invention, analysis can be carried out, for example, by analyzing the content of soluble aggregates in solution (SMC, assessed using size exclusion chromatography). Preferably, stability for at least four weeks at about -20°C is characterized by a content of less than 1.5% BMC, preferably less than 1% BMC.

A preferred pharmaceutical composition formulation of the antibody construct may, for example, comprise the formulation components described below.

Ready form: potassium phosphate, L-arginine hydrochloride, trehalose dihydrate, polysorbate 80 at pH 6.0.

Other examples of stability evaluation of the antibody design of the invention in the form of headlights

- 40 043309 of the maceutical composition are given in the accompanying examples 4-12. In these examples, embodiments of the antibody constructs of the invention are examined against different stress conditions in different pharmaceutical formulations, and the results are compared with other half-life extending (HLE) formats of bispecific T cell-engaging antibody constructs known in the art. In general, it is understood that antibody constructs having a specific FC modality according to the present invention are generally more stable under a wide range of stress conditions, such as temperature and light stress, compared to antibody constructs having different HLE formats. , and in the absence of any HLE format (i.e., canonical antibody constructs). The specified temperature stability may refer to both reduced (below room temperature, including freezing) and elevated (above room temperature, including temperatures at or above body temperature) temperatures. As one skilled in the art will appreciate, this improved stability against stress, which is difficult to avoid in clinical practice, makes the antibody design safer since fewer degradation products are generated in clinical practice. Accordingly, said increased stability means increased safety.

In one embodiment, an antibody construct of the invention, or an antibody construct produced in accordance with a method of the invention, is provided for use in the prevention, treatment, or amelioration of a proliferative disease, neoplastic disease, viral disease, or immunological disorder.

The formulations described herein are useful as pharmaceutical compositions in the treatment, amelioration, and/or prevention of the pathological condition described herein in a patient in need thereof. The term treatment refers to both therapeutic treatment and prophylactic or preventative measures. Treatment involves the use or administration of a formulated form into the body, isolated tissue or cell of a patient who has a disease/disorder, a symptom of a disease/disorder, or a predisposition to a disease/disorder, for the purpose of treating, curing, mitigating, alleviating, altering, correcting, reducing the intensity, improving or affecting a disease, a symptom of a disease, or a predisposition to a disease.

As used herein, the term amelioration refers to any improvement in a disease state in a patient having a tumor or cancer, or metastatic cancer, as defined hereinafter, by administering an antibody construct in accordance with the invention to the subject in need thereof. Such improvement may also manifest itself as slowing or stopping the progression of the patient's tumor or cancer, or metastatic cancer. As used herein, the term prevention means preventing the occurrence or reappearance of a patient having a tumor or cancer, or metastatic cancer, as defined below herein, by administering to the subject in need thereof an antibody construct in accordance with the invention.

The term disease refers to any pathological condition that would benefit from treatment with an antibody construct or pharmaceutical composition described herein. It includes chronic and acute disorders or diseases, including those pathological conditions that predispose the mammal to the disease in question.

A neoplasm is an abnormal growth of tissue that usually, but not always, forms a mass. When a mass forms, it is also called a tumor. The growths or tumors may be benign, potentially malignant (precancerous), or malignant.

Malignant neoplasms are usually called cancer. They usually invade and destroy surrounding tissue and can form metastases, i.e. they spread to other parts, tissues or organs of the body. Therefore, the term metastatic cancer includes metastases to tissues or organs other than those containing the original tumor. Lymphomas and leukemias are lymphoid neoplasms. For the purposes of this invention they are also included in the terms tumor or cancer.

The term viral disease describes diseases that result from a viral infection in a subject.

As used herein, the term immunological disorder describes, along with the usual definition of the term, immunological disorders such as autoimmune diseases, hypersensitivity, immunodeficiency.

In one embodiment, the invention provides a method of treating or ameliorating a proliferative disease, neoplastic disease, or immunological disease, comprising the step of administering to a subject in need thereof an antibody construct of the invention or a construct produced in accordance with a method of the invention.

The terms subject in need or in need of treatment include those who already have

- 41 043309 violation, as well as those who need to prevent a violation. The subject or patient in need includes humans or other mammalian subjects who are receiving prophylactic or therapeutic treatment.

The antibody designs of the invention are generally designed for specific routes and methods of administration, for specific dosages and frequencies of administration, for specific treatment options for specific diseases, with specific ranges of bioavailability and persistence in the body, among other things. The composition materials are preferably formulated in concentrations that are appropriate for the given site of administration.

Thus, formulations and compositions can be prepared in accordance with the invention for delivery by any suitable route of administration. In the context of this invention, routes of administration include, but are not limited to, local routes (such as cutaneous, inhalation, nasal, ocular, auricular/ear, vaginal, mucosal);

enteral routes (such as oral, gastrointestinal, sublingual, sublabial, buccal, rectal);

parenteral routes (such as intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, epidural, intrathecal, subcutaneous, intraperitoneal, extra-amniotic, intraarticular, intracardiac, intradermal, intralesional, intrauterine, intravesical, intravitreal, transdermal, intranasal, transmucosal, intrasynovial , intraluminal ).

The pharmaceutical compositions and antibody constructs of the present invention are particularly useful for parenteral administration, for example, subcutaneous or intravenous delivery, for example, by injection, such as bolus injection, or by infusion, such as continuous infusion. Pharmaceutical compositions can be administered using a medical device. Examples of medical devices for administering pharmaceutical compositions are described in US Pat. No. 4,475,196; 4439196; 4447224; 4447233; 4486194; 4487603; 4596556; 4790824; 4941880; 5064413; 5312335; 5312335; 5383851 and 5399163.

In particular, the present invention provides continuous administration of a suitable composition. By way of non-limiting example, continuous or substantially continuous, i.e. continuous administration can be achieved by using a small pump system worn by the patient to meter the delivery of the therapeutic agent into the patient's body. A pharmaceutical composition containing the antibody construct of the invention can be administered using these pumping systems. In general, such pumping systems are known in the art, and their operation is usually based on periodic replacement of cartridges containing the therapeutic agent to be infused. Replacing the cartridge in such a pumping system entails a temporary interruption or some other interruption in the flow of the therapeutic agent into the patient's body. In such a case, the administration phase before cartridge replacement and the administration phase after cartridge replacement are still considered within the meaning of the pharmaceutical agents and methods of the invention, which together constitute one continuous administration of such therapeutic agent.

Long-term or continuous administration of the antibody constructs of the invention may be intravenous or subcutaneous and accomplished by means of a fluid delivery device or small pumping system, including a fluid guiding mechanism for directing the fluid from the reservoir and an actuator mechanism for actuating the guiding mechanism. Subcutaneous pump systems may include a needle or cannula to pierce the patient's skin and deliver a suitable composition into the patient's body. These pumping systems can be directly attached or attached to the patient's skin independently of the veins, arteries and blood vessels, thereby providing direct contact between the pumping system and the patient's skin. The pump system can be attached to the patient's skin for 24 hours to several days. The pumping system may be small in size with a reservoir for small volumes. As a non-limiting example, the volume of the reservoir for administration of a suitable pharmaceutical composition may range from 0.1 to 50 ml.

Long-term administration can also be accomplished by the transdermal route via a patch worn on the skin and replaced at regular intervals. Suitable patch-based drug delivery systems are known to one skilled in the art for this purpose. It should be noted that transdermal administration is particularly suitable for continuous administration, since replacement of the first spent patch can advantageously be carried out simultaneously with the placement of a new, second patch, for example, on the surface of the skin, immediately adjacent to the first spent patch and immediately before removal of the first spent patch. There are no problems with interruption of flow or termination of the feed cell.

If the pharmaceutical composition has been lyophilized, the lyophilized material is first reconstituted in an appropriate liquid before administration. Lyophilized material can be

- 42 043309 reconstitute, for example, in bacteriostatic water for injection (BVDI), physiological saline solution, phosphate-buffered saline (PBS) or in the same composition in which the protein was before lyophilization.

The compositions of this invention can be administered to a subject at an appropriate dose, which can be determined, for example, through dose escalation studies by administering increasing doses of an antibody construct of the invention described herein that demonstrates cross-species specificity to non-chimpanzee primates, for example, macaques. As stated above, the antibody construct of the invention described herein, demonstrating cross-species specificity, can advantageously be used in identical form in preclinical studies in non-chimpanzee primates and as a drug in humans. The dosage regimen is determined by the attending physician and clinical factors. As is well known in the medical field, dosages for any patient depend on many factors, including the patient's weight, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other concurrently administered drugs.

The term effective dose or effective dosage is defined as an amount sufficient to achieve or at least partially achieve the desired effect. The term therapeutically effective dose is defined as an amount sufficient to cure or at least partially abort a disease and its complications in a patient who is already suffering from the disease. Amounts or dosages effective for this use depend on the disease state (indication) being treated, the antibody construct being delivered, the therapeutic context and objectives, the severity of the disease, previous therapy, the patient's clinical history and response to the therapeutic agent, route of administration, size ( body weight, body surface area or organ size) and/or condition (age and general health) of the patient, and the general condition of the patient's own immune system. The appropriate dose can be adjusted according to the judgment of the attending physician so that it can be administered to the patient at a time or through a series of administrations and in order to obtain an optimal therapeutic effect.

A typical dosage may range from about 0.1 μg/kg to about 30 mg/kg or more, depending on the above factors. In specific embodiments, the dosage may range from 1.0 μg/kg to about 20 mg/kg, optimally from 10 μg/kg to about 10 mg/kg, or from 100 μg/kg to about 5 mg/kg.

A therapeutically effective amount of the antibody construct of the invention preferably results in a reduction in the severity of symptoms of a disease, an increase in the frequency or duration of asymptomatic periods, or the prevention of impairment or disability due to disease involvement. For the treatment of tumors expressing target cell antigen, a therapeutically effective amount of an antibody construct of the invention, e.g., an anti-target cell antigen/CD3 antibody construct, preferably inhibits cell growth or tumor growth by at least about 20%, by at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to untreated patients. The ability of a compound to inhibit tumor growth can be assessed in an animal model predictive of efficacy.

The pharmaceutical composition can be administered as a single therapeutic agent or in combination with additional therapeutic options, such as anti-cancer therapy, if necessary, for example, other protein and non-protein drugs. These drugs may be administered concomitantly with a composition containing an antibody construct of the invention as defined herein, or separately, before or after administration of said antibody construct at specific time intervals and at specific dosages.

As used herein, the term effective and non-toxic dose refers to a tolerable dose of the antibody construct of the invention that is high enough to result in the destruction of pathological cells, tumor elimination, tumor shrinkage, or disease stabilization with little or no major toxicity. Such effective and non-toxic doses can be determined, for example, using dose escalation studies described in the art, and should be below the dose that induces serious adverse side effects (dose limiting toxicity, DLT).

As used herein, the term toxicity refers to the toxic effect of a drug as manifested by adverse events or serious adverse events. These side effects may relate to the lack of tolerability of the drug in general and/or the lack of local tolerability after administration. Toxicity may also include teratogenic or carcinogenic effects caused by the drug.

As used herein, the term safety, in vivo safety, or tolerability defines the administration of a drug product without inducing serious adverse events immediately after administration (local tolerability) and over a longer period of drug use. Safety, in vivo safety or tolerability

- 43 043309 can be assessed, for example, at regular intervals during treatment and in the period following it. Measurements include clinical assessment, such as organ manifestations, and examination of laboratory abnormalities. Clinical evaluation may be performed and abnormal findings recorded/coded according to NCI-CTC and/or MedDRA standards. Organ manifestations may include criteria such as allergy/immunology, blood/bone marrow, cardiac arrhythmia, coagulation, and the like, as described, for example, in the Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Laboratory parameters that can be examined include, for example, hematology, clinical chemistry, coagulation profile and urinalysis, as well as examination of other body fluids such as serum, plasma, lymphatic or cerebrospinal fluid, cerebrospinal fluid and the like. Thus, safety can be assessed, for example, through physical examination, imaging techniques (i.e. ultrasound, X-ray, CT scans, magnetic resonance imaging (MRI), other measurements using technical devices (i.e. electrocardiogram ), vital signs, by measuring laboratory parameters and recording adverse events. For example, adverse events in non-chimpanzee primates in the applications and methods of the invention can be examined by histopathological and/or histochemical methods.

The above terms are also listed, for example, in Preclinical safety evaluation of biotechnology-derived Pharmaceuticals S6; ICH Harmonized Tripartite Guideline; ICH Steering Committee meeting on July 16, 1997.

Finally, the invention provides a kit comprising an antibody construct of the invention or prepared in accordance with a method of the invention, a pharmaceutical composition of the invention, a polynucleotide of the invention, a vector of the invention, and/or a host cell of the invention.

In the context of this invention, the term kit means two or more components, one of which corresponds to an antibody construct, pharmaceutical composition, vector or host cell according to the invention, packaged together in a container, receptacle or otherwise. Therefore, a kit can be described as a collection of products and/or accessories sufficient to achieve a specified purpose, which can be sold as a separate unit.

The kit may contain one or more receptacles (such as vials, ampoules, containers, syringes, bottles, bags) of any suitable shape, size and material (preferably waterproof, such as plastic or glass) containing the antibody construct or pharmaceutical composition according to this the invention in a dosage suitable for administration (see above). The kit may further comprise directions for use (e.g., in the form of a package insert or instructions for use), means for administering the antibody construct of the invention, such as a syringe, pump, infusion device, and the like, means for reconstituting the antibody construct of the invention, and/or means for diluting the antibody construct of the invention.

The invention also provides kits for a single-dose administration device. The kit of the invention may also comprise a first receptacle containing a dried/lyophilized antibody construct and a second receptacle containing an aqueous formulation. In certain embodiments of the present invention, kits are provided containing single and multi-chamber prefilled syringes (eg, liquid syringes or lyophilisate syringes).

It should be noted that, as used herein, singular forms include the plural unless the context clearly indicates otherwise. Thus, for example, a reference to a reagent includes one or more of such different reagents, and a reference to a method includes a reference to equivalent steps and methods known to those skilled in the art that may be modified or substituted for the methods described herein.

Unless otherwise specified, the term at least preceding a series of elements should be understood to refer to each element in the series. Those skilled in the art will recognize or be able to determine, using merely routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be included in this invention.

As used herein, the term and/or includes the meaning and, or and all or any combination of elements united by the specified term.

As used herein, the term about or about means within 20%, preferably within 10%, and more preferably within 5% of a given value or range. Moreover, it also includes a specific number, for example, about 20 includes 20.

The terms less than or greater than include a specific number. For example, less than 20 means less than or equal to. Likewise, more than or greater than means more than or equal to or greater than or equal to, respectively.

In the text of the description and in the claims below, unless otherwise follows from the context,

- 44 043309 the word contain and its variations such as contains and containing should be understood to imply the inclusion of a specified integer or stage or group of integers or stages, but not the exclusion of any other integer or stage or group of integers or stages. As used herein, the term containing may be replaced by the term containing or including, or sometimes by the term having.

As used herein, the expression consisting of excludes any element, step or ingredient not specified in the claimed element. As used herein, the expression consisting primarily of does not exclude materials or steps that do not materially affect the essential and novel characteristics of the claimed item.

In each case, any of the terms containing, consisting predominantly of, and consisting of can be replaced by either of the remaining two terms.

It should be understood that this invention is not limited to the specific methodologies, protocols, materials, reagents and substances, etc. described herein and, therefore, may vary. The terminology used in this document is used only for the purpose of describing specific embodiments, and is not intended to limit the present invention, which is defined solely by the claims.

All publications and patents cited in the text of this specification (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), above or below, are incorporated herein by reference in their entirety. Nothing herein should be construed as an admission that the present invention is not entitled to be opposed to such description based on an earlier invention. To the extent that material incorporated by reference is inconsistent with or inconsistent with this description, this description takes precedence over any such material.

A better understanding of the present invention and its advantages will be provided by the following examples, which are provided for illustrative purposes only. The examples are not intended to limit the scope of the present invention in any way.

Example 1 BiTE®-induced CD69 expression on T cells in the absence of target cells.

Isolated PBMCs from healthy human donors were cultured with increasing amounts of bispecific HLE antibody constructs to CDH19/CD3 or MSLN/CD3 for 48 hours. Expression of the activation marker CD69 on T cells was determined using immunostaining and flow cytometry and antigen-specific mAb conjugates.

Target-independent T cell activation in the context of CD69 up-regulation was observed for all anti-CDH 19 constructs, but was most pronounced for hetero-Fc and crosstel molecules. Upregulation of CD69 by the anti-CDH19-scFc construct occurred at higher concentrations and the amplitude was slightly lower compared to other Fc-based constructs.

With the anti-MSLN constructs, virtually no target-independent T cell activation was observed for the scFc-containing molecule, whereas the hetero-Fc construct induced a strong upregulation of CD69 on the cell surface of T cells in the absence of target cells.

Target-independent T cell activation induced by BiTE® constructs containing a single-chain Fc or hetero-Fc fusion at the C-terminus was assessed for the following constructs:

BiTE® constructs (serial dilutions: 0.1 pM - 2 µM)

a. MSLN scFc; 1.14 mg/ml;

b. MSLN hetero-Fc; 1.02 mg.

Effector cells - human PBMCs (3 donors; #065, #823, #836 (scFc) #401, #415, #433 (hetero-Fc); #590, #595, 598, #605 (X-body)) .

Incubation time - 48 hours.

Determination of CD69 expression on CD4+ and CD8+ T cells using flow cytometer and antigen-specific mAb conjugates. See the results in Fig. 2.

Target-independent T cell activation induced by BiTE® antibody constructs containing a single-chain Fc, hetero-Fc, or C-terminal crossbody fusion was assessed for the following constructs:

BiTE® antibody constructs (serial dilutions: 0.1 pM - 2 µM)

c. CDH19 scFc; 245.3 µg/ml,

d. CDH-19 hetero-Fc; 1 mg/ml,

e. CDH19 X-body; 6.3 mg/ml.

Effector cells are human PBMCs (from 3 to 4 donors; #386, #392, #401 (scFc) #282, #284, #287 (hetero-Fc)).

Incubation time - 48 hours.

Determination of CD69 expression on CD4+ and CD8+ T cells using flow cytometer and antigen-specific mAb conjugates. See the results in Fig. 3.

Target-independent T cell activation in the context of CD69 up-regulation was observed for several bispecific constructs tested in these assays. CD69 up-regulation was generally more pronounced for canonical BiTE® antibody constructs, hetero-Fc molecules and crossbodies compared to the corresponding scFc constructs. Upregulation

CD69 scFc constructs occurred generally at slightly higher concentrations and the amplitude was slightly lower compared to the other two Fc-based constructs.

No target-independent T cell activation was observed with the anti-CDH19-scFc construct, whereas the hetero-Fc and X-body constructs induced a strong upregulation of CD69 on the cell surface of T cells in the absence of target cells.

In addition, target-independent upregulation of CD69 was not observed in the assay using anti-CD33 and anti-Flt-3 constructs. Due to target expression on myeloid lineage cells, these cells were removed before analysis. These data suggest that interaction of the Fc regions of bispecific constructs with FcyR-expressing cells may be responsible for the target-independent induction of CD69 on T cells.

The strong upregulation of CD69 on T cells by the anti-CD70-scFc construct in the absence of tumor cell lines is due to the expression of CD70 on T cells.

Materials and methods.

1. CD19.

Target-independent T cell activation induced by BiTE® antibody constructs containing single chain Fc for the following construct:

1. BiTE® antibody design (serial dilutions: 1.3 pM - 20 nM).

1. CD19-scFc.

2. Effector cells - human PBMCs (3 donors).

3. Incubation time - 48 hours.

4. Flow cytometric analysis of CD69 expression on CD4+ and CD8+ T cells using PE-Cy7-conjugated mAb specific for CD69.

2. CD20.

Target-independent T cell activation induced by BiTE® antibody constructs containing a single-chain Fc, hetero-Fc, or C-terminal crossbody fusion was assessed for the following constructs:

1. BiTE® antibody constructs (serial dilutions: 1.3 pM - 20 nM).

1. CD20-hetFc (hetero-Fc).

2. CD20-scFc.

3. CD20-X body (CD20 crossbody).

2. Effector cells - human PBMCs (3 donors).

3. Incubation time - 48 hours.

4. Flow cytometric analysis of CD69 expression on CD4+ and CD8+ T cells using PE-Cy7-conjugated mAb specific for CD69.

3. CD33.

Target-independent T cell activation induced by BiTE® antibody constructs containing a single-chain Fc, hetero-Fc, or C-terminal crossbody fusion was assessed for the following constructs:

1. BiTE® antibody constructs (serial dilutions: 1.3 pM - 20 nM).

1. CD33-canonical.

2. CD33-scFc.

3. CD33-hetFc.

4. CD33-X body.

2. Effector cells - human PBMCs (3 donors).

3. Incubation time - 48 hours.

4. Flow cytometric analysis of CD69 expression on CD4+ and CD8+ T cells using PE-Cy7-conjugated mAb specific for CD69.

4. CDH19.

Target-independent T cell activation induced by BiTE® antibody constructs containing a single-chain Fc, hetero-Fc, or C-terminal crossbody fusion was assessed for the following constructs:

1. BiTE® antibody constructs (serial dilutions: 1.3 pM - 20 nM).

1. CDH19-scFc.

2. CDH19-hetFc.

3. CDH19-X-body.

2. Effector cells - human PBMCs (3 donors).

3. Incubation time - 48 hours.

4. Analysis by flow cytometry of CD69 expression on CD4+ and CD8+ T cells using

- 46 043309 by using a PE-Cy7-conjugated mAb specific for CD69.

5. MSLN.

Target-independent T cell activation induced by BiTE® antibody constructs containing a single-chain Fc, hetero-Fc, or C-terminal crossbody fusion was assessed for the following constructs:

1. BiTE® antibody constructs (serial dilutions: 1.3 pM - 20 nM).

1. MSLN-scFc.

2. MSLN-hetFc.

3. MSLN-X-body.

2. Effector cells - human PBMCs (3 donors).

3. Incubation time - 48 hours.

4. Flow cytometric analysis of CD69 expression on CD4+ and CD8+ T cells using PE-Cy7-conjugated mAb specific for CD69.

6. EGFRvIII.

Target-independent T cell activation induced by BiTE® antibody constructs containing single-chain Fc or hetero-Fc was assessed for the following constructs:

1. BiTE® antibody constructs (serial dilutions: 1.3 pM - 20 nM).

1. EGFRvIII-canonical.

2. EGFRvIII-scFc.

3. EGFRvIII-hetFc.

2. Effector cells - human PBMCs (3 donors).

3. Incubation time - 48 hours.

4. Flow cytometric analysis of CD69 expression on CD4+ and CD8+ T cells using PE-Cy7-conjugated mAb specific for CD69.

7. DLL3.

Target-independent T cell activation induced by BiTE® antibody constructs containing single-chain Fc or hetero-Fc was assessed for the following constructs:

1. BiTE® antibody constructs (serial dilutions: 1.3 pM - 20 nM).

1. DLL3-canonical.

2. DLL3-scFc.

3. DLL3-hetFc.

2. Effector cells - human PBMCs (3 donors).

3. Incubation time - 48 hours.

4. Flow cytometric analysis of CD69 expression on CD4+ and CD8+ T cells using PE-Cy7-conjugated mAb specific for CD69.

8. CD70.

Target-independent T cell activation induced by BiTE® antibody constructs containing single chain Fc was assessed for the following construct:

1. BiTE® antibody design (serial dilutions: 1.3 pM - 20 nM).

1. CD70-scFc.

2. Effector cells - human PBMCs (3 donors).

3. Incubation time - 48 hours.

4. Flow cytometric analysis of CD69 expression on CD4+ and CD8+ T cells using PE-Cy7-conjugated mAb specific for CD69.

9.FLT3.

Target-independent T cell activation induced by BiTE® antibody constructs containing single chain Fc was assessed for the following construct:

1. BiTE® antibody design (serial dilutions: 1.3 pM - 20 nM).

1. FLT3-scFc.

2. Effector cells - human PBMCs (3 donors; without CD14+/CD33+ cells).

3. Incubation time - 48 hours.

4. Flow cytometric analysis of CD69 expression on CD4+ and CD8+ T cells using PE-Cy7-conjugated mAb specific for CD69.

Example 2.

Purified BiTE® antibody constructs were applied to a Maxisorb plate at decreasing concentrations (100 nM, 1:4 dilution). After 3 washes with PBS-T and blocking with PBS/3% (wt/vol) BSA (60 min, 37°C), pooled human plasma was incubated for 60 min at 80 rpm at room temperature. After 3 washes, a mouse monoclonal antibody specific for human C1q subunit A (CC1q) (Thermo MA1-83963, 1:500) was added for 60 min, at 80 rpm at room temperature, after the wash steps described, goat anti-mouse FcPOX mAb (1:5000) were incubated for 60 min at 80 rpm at room temperature. After

- 47 043309 additional washing was incubated with TMB substrate and stopped after the colorimetric reaction by adding H ₂ SO ₄ . Absorbance was determined at 450 nm.

Result. As shown in FIG. 4, at high concentrations, the hetero-Fc-based BiTE® construct (squares) exhibited higher binding signals toward human CClq compared to the single-chain Fc-based BiTE® construct (triangles). Canonical BiTE® (circles) was used as a negative control and did not show significant CClq binding.

Example 3: Pharmacokinetics of BiTE® Antibody Constructs Fused with Half-Life Extending Modalities.

Various BiTE® antibody target binding constructs were fused with four different half-life extending components. All different HLE variants available for the BiTE® antibody construct were examined in cynomolgus monkeys in the context of pharmacokinetic (PK) studies. They were successively named BiTE®-scFc, BiTE®-hetFc, BiTE®-HALB, B1TE®-X-body, as well as canonical BiTE®, according to the half-life-extending modality attached to the target binding construct. The corresponding nomenclature of these molecules is summarized in Table. 4 below.

Table 4

BiTE® Single-Dose Antibody Construct Compound Nomenclature

synonym for connection name of test compound Compound 1a CD33-scFc Connection 1b CD33-hetFc Connection 1s CD33-HALB Connection 2a MSLN-scFc Connection 2b MSLN-hetFc Connection 2c MSLN-HALB 2d connection MSLN-X-body Connection For CDH19-scFc Connection 3b CDH19-hetFc Connection Zs CDH19-HALB 3d connection CDH19-H6 Connection 4a CD20-scFc Connection 4b CD20-hetFc Connection 5a DLL3-scFc Connection 5b DLL3-hetFc Connection 5c DLL3-HALB Connection 6a EGFRvIIICC-SCFC Connection 6b EGFRvIIIcc-HALB Connection 7 FLT3-scFc Connection 8 CD70-scFc Connection 9 CD19cc-scFc

BiTE®-HLE antibody constructs were administered as an intravenous bolus injection (compounds lb, 2a-d, 3a/b, 4a/b, 5a-5c, 7-9) and intravenous infusion (compounds 1a, 1c, 3c/d, ba /b, each as a 30-minute infusion). BiTE® antibody constructs were administered over a linear, pharmacokinetically relevant dose range of 3 μg/kg to 6 μg/kg, 12 μg/kg, and 15 μg/kg, respectively.

To allow comparison, the reported serum concentrations are normalized relative to

-48 043309 dose specific and normalized to molecular weight (described in nmoles).

For each of the above compounds, a group of at least two or three animals was studied. Blood samples were collected and serum was prepared to determine serum concentrations. Serum levels of BiTE® antibody constructs were determined using an immunoassay. The assay was performed by capturing the BiTE® antibody construct through its target component, while an antibody directed against the CD3 binding portion of the construct was used for detection. Serum concentration-time profiles were used to determine PK parameters.

The corresponding study configuration was adjusted for the characteristics of the BiTE® antibody constructs.

The duration of the study was 1 week or 2 weeks. The timing of blood sample collection may vary slightly and is given for both configurations in Table. 5 below.

Table 5 Time of blood sample collection during PK studies. Time may vary between single studies. The times indicated by an asterisk are mandatory and generally accepted for all studies.

blood sample collection time 1 week study duration [h] blood sample collection time 2-week duration [h] 0.05/0.085* 0.05/0.085* 0.25 0.25 0.5 0.5 1 1 2 2 4* 4* 8 8 16 16 24* 24* 48* 48* 72* 72* 96 96 120 120 144 144 168* 168* 216 240 264 336*

The pharmacokinetics of sixteen BiTE®-HLE antibody constructs are provided as examples. Each compound group represents one BiTE® antibody construct fused to a scFc-, hetFc-, HSA- (human albumin), or crosstelo-Fc format. For all proteins, serum levels were quantifiable at all time points in all animals after administration of the BiTE®-HLE antibody construct. PK profiles show a biphasic, exponential decrease following administration of each individual test compound (Figure 5).

Pharmacokinetic parameters were determined using standard noncompartmental analysis (NCA) methods. Using non-compartmental analysis, the following PK parameters were assessed: PPKb _esc . (area under the serum concentration-time curve), Vss (volume of distribution at steady state), C _L (systemic elimination) and terminal t _1/2 (terminal half-life).

The PK parameters for each test compound are summarized as an average over n=2 and n=3, respectively, in Table. 6 below.

- 49 043309

Table 6

Pharmacokinetic parameters of different HLE variants for different target-binding BiTE® constructs in cynomolgus monkeys__________________

and with the following connection terminal tl/2 [h] AUC^ _esk- [normalization to 15 mcg/kg] [h*ng/ml] C1 [ml/h/kg] Vss [ml/kg] Compound 1a 167 9981 1.4 256 Compound 1b 95 6159 2.4 235 Connection 1s 47 4498 3.3 161 Connection 2a 213 41173 0.4 89 Connection 2b 116 18745 0.8 78 Connection 2c 77 28928 1.0 65 2d connection 77 9825 1.5 112 Connection For 61 4109 3.7 129 Connection 3b 59 4561 3.3 78 Connection Zs 51 2769 6.8 299 3d connection 3 510 30, 0 653 Connection 4a 97 7816 1.9 181 Connection 4b 62 3606 4.2 292 Connection 5a 234 30954 0.5 144 Connection 5b 173 18299 0.8 166 Connection 5c 142 26418 0.6 103 Connection 6a 97 15854 1.0 103 Connection 6b 48 77271 1.0 64 Connection 7 64 1971 7.6 395 Connection 8 122 17093 0.9 119 Connection 9 210 6729 2.2 540

Overall, the AUC _{of besk} for different target binding BiTE® fused to -scFc, -hetFc, HSA- or crosstelo-HLE modality, respectively, ranged from 1971 h*ng/ml to 77271 h*ng/ml depending on BiTE® target type. All HLE fusions analyzed achieved systemic clearance values ranging from 0.4 to 7.6 ml/h/kg. The corresponding volume of distribution ranged from 64 to 540 ml/kg. Compound 3d, the canonical BiTE® target binding compound 3 without half-life extension, is included as a standard. BiTE® antibody designs without half-life extension exhibit rapid clearance, low serum abundance, and resulting short terminal half-life. Comparisons of terminal half-life depending on modality are summarized in Table. 7.

-50043309

Table 7

Comparison of terminal half-life depending on modality

After studying up to four half-life extending (HLE) components for each BiTE® targeting, it is clear that the -scFc component shows an increase in t _1/2 compared to corresponding other half-life extending components after administration of a single low dose of 6, 10, 12 and 15 µg/kg (see Fig. 6).

Example 4.

Preformulated drugs containing purified MSLN-hALB, MSLN-hFc, and MSLN-scFc constructs, respectively, were buffer exchanged by ultrafiltration/diafiltration using membranes with a nominal molecular weight cutoff (NOMC) of 10 kDa. The final finished form was obtained by adding concentrated stock solutions. The resulting finished forms for each design are shown in Table. 8. The concentration of the target protein was 1.0 mg/ml. The prepared MSLN constructs were poured to 1 mL into Type I glass vials, which were sealed with butyl rubber stoppers and crimped with aluminum caps. Filled vials were incubated at 20, 5, 25 and 37°C. One vial of each version was subjected to five freeze-thaw (F/T) cycles. The target freezing temperature was 29°C. The target defrost temperature was 2°C. The rate of change was approximately 0.3 K/min.

Trained personnel assessed visible particles according to the method described in Ph Eur 2.9.20. The number of visible particles per bottle is given in the table. 8. The number of visible (larger than 125 μm) protein particles was greater for the MSLN-hFc construct compared to both the MSLN-hALB and MSLN-scFc constructs.

Table 8

Number of visible protein particles per vial for stressed and unstressed (T0) samples containing different BiTE® anti-mesothelin (MSLN) extended half-life constructs

Design hALB hFc scFc Finished form K60RTrT K60RTrT G40MSUT K60RTrT G40MSUT Number of visible (>125 µm) protein particles per vial THAT 0 0 1 0 0 5 cycles Z/R 0 2 2 0 1 2n 5°C 0 2 2 0 0 2n 25°С 0 2 1 0 0 2n 37°С 0 2 2 0 0 4n -20°С 0 2 1 0 0 4n 5 °C 0 1 2 0 0 4n 25°С 0 2 2 0 0 4n 37°С 0 2 2 0 0

The above samples were also analyzed by size exclusion ultra-high performance chromatography (SEC-UPLC) to quantify the percentage of high molecular weight components (HMCS). EC-UPLC was performed on an AcquityH-Class UPLC system (Waters) using a 150 mm Acquity UPLC BEH200 SEC column (Waters). The column temperature was set to 25°C. Separation of size variants was ensured using the isocratic method with a flow rate of 0.4 ml/min. The mobile phase consisted of 100 mM sodium phosphate, 250 mM NaCl at pH 6.8. Analysis time was 6.0 min overall. Samples were kept at 8°C in an autosampler until analysis. A total amount of protein of 3 μg was injected. To avoid contamination, an intermediate injection of 40% acetonitrile was performed after each sample. Detection was based on fluorescence emission (excitation at 280 nm, emission at 325 nm). Peak integration was performed using Empower® software. The relative area under the ICH curve is presented in Table. 9.

Fc-based constructs exhibited lower VMC content in the G40MSuT formulation than in K60RTrT, regardless of stress conditions. It became apparent that the MSLN-scFc construct contained less ICH than MSLN-hFc in both G40MSuT as well as K60RTrT preparations. MSLN-scFc in its preferred formulation (G40MSuT) was less prone to ICH formation than MSLN-hALB prepared in K60RTrT. In previous experiments, this buffer demonstrated improved stabilization potential for hALB-based constructs.

Table 9

Summarized information on the content of HMC in stressed and non-stressed (SS) MSLN hALB, hFc and -scFc preparations determined using SEC-UPLC

Design hALB hFc scFc Ready form K60RTrT K60RTrT G40MSuT K60RTrT G40MSuT %vmk That 18 6.7 3.3 2.5 1.3 5 cycles 3/P 2.0 7.2 4.1 3.0 1.5 2n 5°C n. And. N. AND - n. And. 2.9 1.1 2n 25°С n. And. 6, 6 2.7 2.4 0.5 2n 37°С 2, 6 6.3 2.1 2.7 0.3 4n -20°С 5, 9 8.7 1.6 6, 6 0.3 4n 5°C 2.0 8.2 2.8 3.6 0.6 4n 25°С 2.2 6.8 2.6 2.7 0.4 4n 37°С 3.5 7.6 1.9 4.3 0.3

n.i. = not studied.

The prevalence of chemical modifications after heat stress (incubation at 37°C) was monitored using peptide mapping. Protein samples were enzymatically digested and the resulting peptides were separated using reverse phase chromatography. The eluate from the column was injected directly into the ion source of the mass spectrometer to identify and quantify peptides.

To achieve maximum coverage, two separate enzymatic digestions were performed: one with trypsin and one with chymotrypsin. In each case, the proteins were denatured with guanidinium chloride and then reduced with dithiothreitol (DTT). After incubation in DTT, free cysteine residues were alkylated by adding iodoacetic acid. Samples were then buffer exchanged to 50 mM Tris, pH 7.8, for digestion. Trypsin and chymotrypsin were added to separate reaction tubes at a ratio of 1:10 (sample:enzyme) each. The samples were digested for 30 min at 37°C and the reaction was quenched by adding trifluoroacetic acid.

μg of each digestion product was separately injected onto a Zorbax SB-C18 reverse-phase column (Agilent #859700-902) equilibrated in 0.1% (v/v) formic acid (FA). A 156-min gradient of up to 90% acetonitrile containing 0.1% LA was used to elute peptides directly into the electrospray ion source of a Q-Exactive Plus mass spectrometer (Thermo Scientific). Data were acquired in a data-dependent mode using the top-12 method, in which a full scan (resolution 70,000; scan range 200 2000 m/z) is followed by high-energy collision-induced dissociation (HCD) of the 12 most abundant ions (resolution 17,500).

Peptides were identified based on accurate mass and tandem mass spectra using in-house software. Identification results were confirmed manually. Relative amounts of modified and unmodified peptides were calculated from ion abundance using Pinpoint software (Thermo Scientific).

The percentage of chemical modifications of complementarity determining regions (CDRs) and half-life extending moieties (hALB or Fc) determined in MSLN-hALB preparations

-52043309

-hFc and -scFc, shown in table. 10. When comparing similar preparation conditions, it is apparent that, overall, chemical modifications were the least common in scFc constructs.

Table 10

Summary of chemical modifications in stressed and non-stressed (T0) MSLN-hALB, -hFc, and -scFc preparations determined by peptide mapping

Design hALB hFc scFc Ready form K60RTrT K60RTrT G40MSuT K60RTrT G40MSuT %N101 deamidation (CDR) THAT oh 1 0.2 0.2 0.2 0.2 2n 37°С 0.7 0.8 thirty 0.7 3.2 4n 37°С 1.3 H. AND - 8.5 H. And . 6.4 %N162 deamidation (CDR) THAT thirty 1.7 19 2.3 2.5 2n 37°С 15.9 11.6 2.7 15.0 3.3 4n 37°С 26.8 n. And . 3.7 n. And . 4.1 %M27 9 oxidation (CDR) THAT 0.6 1.4 16 0.6 ι,ο 2n 37°С 1.2 0.8 0.8 0.6 ι,ο 4n 37°С 0.9 Η. AND - 0.8 Η. And . 0.6 %N348 deamidation (CDR) THAT 0.5 3.2 3.3 0.5 0.9 2n 37°С 20.5 21.6 19 9.4 1.3 4n 37°С 22.8 n. And . 2.0 n. And . 2.9 %N351 deamidation (CDR) THAT 0.2 2.9 2, 6 0.5 ι,ο

- 53 043309

2n 37°С 6, 6 12.7 0.9 h, 8 0.4 4n 37 ⁵ C 8.7 n. And. 0.8 n. And. 0.8 %M530 oxidation (Fc) THAT n. P. 3.9 4.1 2, 6 3.2 2n 37 n. P. 9.0 3, 1 4, 0 4.3 4n 37 n. P. n. And. 3, 4 n. AND . 3.5 %N603 deamidation (Fc) I THAT n. P. 1.3 19 1, 3 1.4 2n 37 ⁵ C n. P. 7.9 4, 6 7, 0 5.6 4n 37 ³ C n. P. n. And. 6, 9 n. And. 8.1 %M706 oxidation (Fc) THAT n. P. 3.2 3, 6 1, . 5 2.1 2n 37 ³ C n. P. 6.0 2.8 2, . 1 2.5 4n 37' ³ C n. P. n. And. 2, 6 n. AND . 2.0 %M587 oxidation (hALB) THAT 10 n. P. n. P. n. P. n. P. 2n 37' ³ C 2.2 n. P. n. P. n. P. n. P. 4n 37' ³ C 2.3 n. P. n. P. n. P. n. P. %M623 oxidation (hALB) THAT 19 n. P. n. P. n. P. n. P. 2n 37' ^Z s 2.4 n. P. n. P. n. P. n. P. 4n 37' ^Z s thirty n. P. n. P. n. P. n. P. %M798 oxidation (hALB) THAT 14 n. P. n. P. n. P. n. P. 2n 37' ^Z s 3.3 n. P. n. P. n. P. n. P. 4n 37' ^Z s 3.5 n. P. n. P. n. P. n. P. %M8 2 9 oxidation (hALB) THAT 8.9 n. P. n. P. n. P. n. P. 2n 37‘ ^Z s 42.9 n. P. n. P. n. P. n. P. 4n 37' ^Z s 44.1 n. P. n. P. n. P. n. P.

n.p. = not applicable; n.i. = not studied.

Example 5.

Constructs MSLN-hALB, -hFc, -scFc, prepared as described in Example 4, were subjected to a pH jump experiment. The concentration of starting materials was 1.0 mg/ml. A volume of 0.38 ml of each starting material was poured into a glass vial. After preconditioning at 37°C, the solutions were supplemented with a 20-fold volume of phosphate-buffered saline (PBS), which consisted of 0.090 M potassium phosphate, 0.480 M sodium phosphate (both dibasic), 0.052 M potassium chloride, and 2.76 M NaCl. The supplemented samples were incubated at 37°C for two weeks. After incubation, they were analyzed by EC-UPLC using the method described in example 4, and the percentage of VMC is given in table. 11. When comparing all constructs prepared in K60RTrT, the content of VMC increased in the following order: hALB < scFc < hFc. The MSLN-scFc construct also exhibited lower VMC content than MSLN-hFc when prepared in G40MSuT.

Table 11 Generalized information on the content of VMC in the preparations exposed to stress (jump pH+2H 37°C) ______MSLN-hALB, -hFc and -scFc, determined using SEC-UPLC______

Design hALB hFc scFc Ready form K60RTrT K60RTrT G40MSuT K60RTrT G40MSUT %vmk 2n 37°С 1.5 8.3 7.1 5.4 5.1

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Example 6.

The MSLN-hALB, -hFc, -scFc constructs, prepared as described in Example 4, were subjected to shaking stress. The concentration of starting materials was 1.0 mg/ml. A volume of 0.5 ml of each solution was filtered through a corresponding 0.22 μm filter and poured into 3cc glass vials. The vials were placed in a plastic box, ensuring that the vials did not move within the box during shaking. The box was placed on an orbital shaker. Samples were shaken at 500 rpm for 65 hours. Visible particles were assessed according to the method described in Ph Eur 2.9.20. This method was carried out by trained staff. The number of visible particles per bottle is given in the table. 12. Visible protein particles were observed only in MSLN-hFc preparations.

Table 12

Number of visible protein particles per vial in shaken samples

Design hALB hFc scFc Ready form K60RTrT K60RTrT G40MSUT K60RTrT G40MSuT Number of visible (>125 µm) protein particles per vial 65 h, 500 rpm 0 1 1 0 0

The above samples were also analyzed by size exclusion ultra-high performance chromatography (SEC-UPLC) to quantify the percentage of high molecular weight components (HMCS). The same method was used as described in example 4. The content of VMC in the samples after shaking is given in table. 13. ICH formation was most pronounced for the MSLN-hFc construct when comparing K60RTrT preparations. ICHs were more common with the MSLN-hFc construct than with the MLSN-scFc construct.

Table 13

Generalized information on the content of VMC in the MSLN-hALB, -hFc and -scFc preparations exposed to stress (pH + 2H jump 37°C), determined using SEC-UPLC

Design hALB hFc scFc Ready form K60RTrT K60RTrT G40MSuT K60RTrT G40MSuT %vmk 65 h, 500 rpm 18 5.8 2.4 1.8 0.3

Example 7.

The MSLN-hALB, -hFc, -scFc constructs, prepared as described in example 4, were exposed to visible and UVA light (photostress). In all preparations, the total protein concentration was 1 mg/ml. Protein solutions were filtered through a 0.22 μm pore size filter and poured into 0.5 ml type I glass vials. MSLN-hALB and -scFc constructs were subjected to two different tests involving 0.2 μm visible light/25 Wh/ m ² UVA light and 1.2 Mlx visible light/173 Wh/m ² respectively. The MSLN-hFc design was subjected to two different tests involving 0.2 Mlx of visible light without UVA light and 1.2 Mlx of visible light/30 Wh/m ² UVA light, respectively. The temperature in the chamber was set to 25°C. After exposure to light, samples were analyzed by visual inspection (Table 14), EC-UPLC (Table 15) and peptide mapping (Table 16). The above methods were carried out in accordance with the procedures described in Example 4. Although the MSLN-hALB and -scFc target constructs were exposed to higher doses of UVA light, no visible protein particles were observed, whereas the MSLN-hFc samples showed one visible protein particle per vial in both trials, regardless of preparation.

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Table 14

Summarized information on the number of visible protein particles per vial in MSLN-hALB preparations,

-hFc and -scFc determined after light exposure

Design hALB hFc scFc Ready form K60RTrT K60RTrT G40MSUT K60RTrT G40MSUT Number of visible (>125 µm) protein particles per vial THAT 0 0 1 0 0 Test 1 O ¹¹ 1 ² > 1 ² > about ¹¹ about ¹¹ Test 2 about ³ ' ]_ 4) ]_4) about ³ ' about ³ '

1) 0.2 mlk visible light/25 Wh/m2 UVA light, ²⁾ 0.2 mlk visible light without UVA light, ³⁾ 1.2 mlk visible light/173 Wh/ ^m2 , ^{4 )} 1.2 mlk of visible light/30 Wh/ ^m2 .

The amount of VMC increased in the following order: MSLN-hALB < -scFc < -hFc when the protein was prepared in K60RTrT. The amount of VMC could be reduced for Fc-based constructs when prepared in G40MSuT. However, ICHs were again less pronounced for the MSLN-scFc construct. The MSLN-hFc target design was found to be particularly sensitive to exposure to UVA light.

Table 15 Generalized information on the content of VMC in the MSLN-hALB, -hFc and -scFc preparations, ____________ determined after exposure to light using SEC-UPLC____________

Design hALB hFc scFc Ready form K60RTrT KGORTrT G40MSUT KGORTrT G40MSuT %vmk That 1.8 6.7 3, 3 2.5 1.3 Test 1 1.8 ¹¹ 6, 3 ²⁾ 2.5 ²⁾ 2.1 ^1J 0.4 ^υ Test 2 2.0 ³⁾ 11, 0 ⁴⁾ 2.1 ⁴⁾ 2.4 ³⁾ 0.3 ^3>

1G7GT7-----------------, 2 *---------------------------- --------------------) 0.2 mlk visible light/25 Wh/m UVA light, ²⁾ 0.2 mlk visible light without UVA light , ³⁾ 1.2 mlk of visible light/173 Wh/m ² , ⁴⁾ 1.2 mlk of visible light/30 Wh/m ² .

The percentage of chemical modifications of the complementarity determining region (CDR) and half-life extending portion (hALB or Fc) determined in the MSLN-hALB, -hFc and -scFc preparations is given in Table. 16. When comparing similar preparation conditions, it is apparent that, overall, chemical modifications were the least common in scFc constructs.

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Table 16

Summary of chemical modifications in MSLN-hALB, -hFc and -scFc preparations determined after exposure to light using peptide mapping

Design hALB hFc scFc Ready KbOITgT KbOITgT G40MSUT KbOITgT G40MSUT form %N101 deamidation (CDR) THAT oh 1 0.2 0.2 0.2 0.2 Test 1 0.2 ⁴⁾ n. And. 0.3 ²⁾ n. And. 0.5 ⁴⁾ Test 2 0.2 ³ > n. And. 0.6 ⁴ > n. And. 0.7 ³ > %N162 deamidation (CDR) THAT thirty 1.7 19 2.3 2.5 Test 1 3, O ¹ ' n. And. 2.1 ²⁾ n. And. 2.7 ¹ ' Test 2 3.6 ³⁾ n. And. 3.1 ⁴ > n. And. 2.8 ³⁾ %M279 oxidation (CDR) THAT 0.6 1.4 16 0.6 1.0 Test 1 0.8 ¹ ' n. And. 2.6 ²⁾ n. And. 0.6 ¹ ' Test 2 1.0 ³ > n. And. 6.3 ⁴ > n. And. 0.7 ³ > %N348 deamidation (CDR) THAT 0.5 3.2 3.3 0.5 0.9 Test 1 0.4 ¹ ' n. And. 2.7 ² > n. And. 0.2 ⁴ > Test 2 0.9 ³⁾ n. And. 3.9 ⁴ > n. And. 0.2 ³⁾ %N351 deamidation (CDR) THAT 0.2 2.9 2, 6 0.5 1.0 Test 1 0.4 ¹ ' n. And. 2.0 ²⁾ n. And. 0, Z ¹ ' Test 2 0.5 ³ > n. And. 2.6 ⁴⁾ n. And. o, ³ > %M530 oxidation (Fc) THAT n. P. 3.9 4.1 2.6 3.2 Test 1 n. P. n. And. 7.6 ²⁾ n. And. 3, I ¹ ' Test 2 n. P. n. And. 21.8 ⁴⁾ n. And. 4.1 ³ > %M706 oxidation (Fc) THAT n. P. 3.2 3, 6 1.5 2.1 Test 1 n. P. n. And. 6.5 ² > n. And. 1.8 ¹ ' Test 2 n. P. n. And. 17.8 ⁴⁾ n. And. 2.7 ³ > %M587 oxidation (hALB) THAT 10 n. P. n. P. n. P. n. P. Test 1 1.5 n. P. n. P. n. P. n. P. Test 2 2.4 n. P. n. P. n. P. n. P. %M623 oxidation (hALB) THAT 19 n. P. n. P. n. P. n. P. Test 1 4.0 n. P. n. P. n. P. n. P. Test 2 4.1 n. P. n. P. n. P. n. P. %M7 98 oxidation (hALB) THAT 14 n. P. n. P. n. P. n. P. Test 1 2.1 n. P. n. P. n. P. n. P. Test 2 3, 1 n. P. n. P. n. P. n. P. %M8 2 9 oxidation (hALB) THAT 8.9 n. P. n. P. n. P. n. P. Test 1 31.0 n. P. n. P. n. P. n. P. Test 2 25.2 n. P. n. P. n. P. n. P.

n.p. = not applicable; n.i. = not studied.

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Example 8.

The MSLN-hALB construct was prepared in K60RTrT and the MSLN-scFc construct was prepared in G40MSuT according to the procedure described in Example 4. The total protein concentration was 0.05 mg/ml. Glass (borosilicate, type I, 13 mm Zss bottle from West, art. no. 68000375) and polypropylene test containers (2 ml with O-ring, for example from Sarstedt, art. no. 72.694.005) were filled with 500 μl of the test solution. The test solution was left for five minutes in the first test container. A 150 μL aliquot was then removed for analysis. The remaining test solution (350 μl) was sequentially transferred from one test container to the next (five containers in total). The solution was left in each vial for five minutes before the next transfer. The same pipette tip was used for each transfer step. The same test was performed using 30 ml polycarbonate bottles (Nalgene, PCS-000295 with cap, PP/20-415/ZTPE). In the case of this type of container, the first container was filled with 5 ml. After withdrawing a 150 μl aliquot, the remaining volume was transferred from one test container to the next (following the procedure described above). Samples obtained from container #1 and #5 were analyzed by EC-UPLC (using a method similar to that described in Example 4). Additionally, protein detection was performed using a FDM detector (280 nm) to determine the protein concentration. The percentage protein recovery from each test container is given in Table 1. 17. It was shown that protein recovery was more pronounced for the MSLN-scFc construct than for the MSLN-hALB construct, regardless of container type.

Table 17 Protein recovery from different container types for MSLN-hALB and -scFc constructs, ___________determined by EC-UPLC___________

Design hALB scFc Finished form K60RTrT G40MSuT %Protein recovery (from nominal) Type I glass 80.0 92.0 Polypropylene 87.0 97.3 Polycarbonate 87.0 96, 0

Example 9.

The MSLN-hALB construct was prepared in K60RTrT, and the MSLN-scFc construct was prepared in K60RTrT and G40MSuT according to the procedure described in Example 4. The total protein concentration was 1.0 mg/ml. 1950 μl of each test solution was supplemented with 50 μl of 1000 ppm. silicon standard solution (Specpure from AlfaAesar, Art. No. 38717), which resulted in 25 ppm. supplemented sample. The unsupplemented test solution served as a control sample. The spiked test solution and the control sample were poured into Type I glass vials and incubated at 37°C for 24 hours. All samples were analyzed by EC-UPLC according to the method described in Example 4 to estimate the quantities VMC (Table 18). When prepared in K60RTrT, the MSLN-hALB and -scFc constructs showed a similar increase in the number of IMCs after the addition of silicon.

Table 18 Generalized information on the content of VMC in MSLN-hALB and -scFc preparations, determined using SEC-UPLC after addition of 25 ppm silicon

Design hALB scFc Finished form K60RTrT K60RTrT G40MSUT Δ%ICH (compared to non-supplemented control) 25 ppm addition 10 1.0 0.2

Example 10.

Preformulated drugs containing purified CD33cc-hALB, CD33cc-hFc, and CD33cc-scFc constructs, respectively, were buffer exchanged by ultrafiltration/diafiltration using membranes with a nominal molecular weight cutoff (NOMC) of 10 kDa. The final finished form was obtained by adding concentrated stock solutions. The resulting finished forms for each design are shown in Table. 19. The concentration of the target protein was 1.0 mg/ml. The prepared CD33cc- constructs were poured up to 1 ml into Type I glass vials, which were closed with butyl rubber stoppers and crimped with aluminum caps. Filled vials were incubated at -20, 5, 25 and 37°C. One vial of each version was subjected to five freeze-thaw cycles (3/P). Target temperature for

-58 043309 freezing was -29°C. The target defrost temperature was 2°C. The rate of change was approximately 0.3 K/min. The above samples were also analyzed by size exclusion ultra-high performance chromatography (SEC-UPLC) to quantify the percentage of high molecular weight components (HMCS). SEC-UPLC was carried out in accordance with the method described in example 4. When prepared in K60RTrT, the amount of VMC in unstressed samples increased in the following order: scFc < hALB < hFc. The least pronounced increase in the number of ICHs after stress associated with freezing and thawing was observed for the scFc construct. The hFc construct turned out to be the most predisposed to the formation of ICH at 20°C. The content of VMC increased after four weeks of storage at 5°C. ICH formation under these conditions was more pronounced for Fc-based constructs than for albumin-based constructs. In K60RTrT, no significant increase in the amount of VMC was observed at elevated storage temperatures (25 and 37°C). When prepared in G40MSuT, all constructs showed similar VMC content in unstressed samples. The increase during freezing and thawing was more different for Fc-based constructs when compared with albumin-based constructs. In G40MSuT, the hFc design was the least stable when stored at 20°C. A significant increase in the amount of VMC during liquid storage was observed only for the hALB construct.

Table 19

Summarized information on the content of IMC in stressed and non-stressed (T0) CD33cc-hALB, -hFc and -scFc preparations determined using SEC-UPLC

Design hALB hFc scFc Ready form K60RTrT G40MSUT KSORT G40MSUT K60RTrT G40MSUT THAT 1.5 0.3 %vmk 2.7 0.3 1.3 0.3 5 cycles 2.0 0.5 3.1 0.7 1.6 0.7 3/P 2n -20°С n. And. n. And. N. AND - n. And. 1.5 0.5 2n 5°C n. And. n. And. N. AND - n. And. 1.8 0.2 2n 25°С 1.7 0.6 2.3 0.2 1.3 0.2 2n 37°С 19 0.7 1.8 0.2 1.2 0.2 4n -20°С 16 0, 4 4.2 1.5 1.7 0.9 4n 5°C 19 0.3 3.3 0.3 2.1 0.4 4n 25°С 14 0.6 2.2 0.2 1.4 0.4 4n 37°С 1.3 0.7 2.0 0, 1 1.4 0.3

n.i. = not studied.

The prevalence of chemical modifications after heat stress (incubation at 37°C) was monitored using peptide mapping according to the method described in Example 4. Percentage of chemical modifications of complementarity determining regions (CDRs) determined in CD33cc-hALB, -hFc and - preparations scFc, given in table. 20 Overall, CD33cc-scFc constructs exhibited the fewest chemical modifications in the CDR. It became apparent that deamidation at the CDR in particular was least pronounced for the scFc construct.

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Table 20

Summary of chemical modifications in stressed and non-stressed (T0) CD33cc-hALB, -hFc and -scFc preparations determined by peptide mapping

Design hALB hFc scFc Ready K60RTrT G40MSUT K60RTrT G40MSUT K60RTrT G40MSUT form %M34 oxidation (CDR) THAT 1.0 1.8 1.0 1.4 1.7 19 2n 37°С 0.9 1.3 0.9 1.1 1.0 1.7 4n 37°С n. And. n. And. n. And. 16 n. And. 18 %D103 isomerization (CDR) THAT 0.8 0.8 0.8 0.8 0.6 0.6 2n 37°С 4.0 4.6 4.5 4, 4 5.8 7.3 4n 37°С n. And. n. And. n. And. 8.0 n. And. 12.4 %M290 oxidation ( CDR) THAT 0.7 1.4 0.8 1 1.3 14 2n 37°С 0.7 1.0 0.8 0.8 0.8 1.3 4n 37°С n. And. n. And. n. And. 1.2 n. And. 16 %N359 deamidation (CDR) THAT 5.8 11, 4 5.3 6.3 0.4 0.5 2n 37°С 19.3 5.8 11.2 2.8 7.0 0.9 4n 37°С n. And. n. And. n. And. 2, 9 n. And. 2.2 %N362 deamidation (CDR) THAT 5.4 8.7 z, 9 4.0 0.2 0.3 2n 37°С 13.5 3.6 6.7 1.2 3.1 0.3 4n 37°С n. And. n. And. n. And. 1.4 n. And. 0.7

n.p. = not applicable; n.i. = not studied.

Example 11.

The CD33cc-hALB, -hFc and -scFc constructs, prepared as described in Example 4, were subjected to a pH jump experiment. The concentration of starting materials was 1.0 mg/ml. A volume of 0.38 ml of each starting material was poured into a glass vial. After preconditioning at 37°C, the solutions were supplemented with a 20-fold volume of phosphate-buffered saline (PBS), which consisted of 0.090 M potassium phosphate, 0.480 M sodium phosphate (both dibasic), 0.052 M potassium chloride, and 2.76 M NaCl. The supplemented samples were incubated at 37°C for two weeks. After incubation, they were analyzed by EC-UPLC using the method described in example 4, and the percentage of VMC is given in table. 21. The CD33cc-scFc constructs exhibited the lowest BMC content after pH excursion compared to the CD33cc-hALB and -hFc constructs, regardless of preparation.

Table 21

Generalized information on the content of VMC in CD33cc-hALB, -hFc and -scFc preparations exposed to stress (pH jump + 2H 37°C), determined using SEC-UPLC

Design hALB hFc scFc Finished form K60RTrT G40MSuT K60RTrT G40MSuT K60RTrT G40MSUT %vmk 2n 37°С 1.7 4, 8 1.6 1.8 eleven 1.5

Example 12.

The CD33cc-hALB, -hFc and -scFc constructs, prepared as described in Example 4, were subjected to shake stress. The concentration of starting materials was 1.0 mg/ml. A 0.5 mL volume of each solution was filtered through a matching 0.22 μm filter and poured into 3cc Type I glass vials. The vials were placed in a plastic box, ensuring that the vials did not move within the box during shaking. The box was placed on an orbital shaker. The samples were shaken at 500 rpm for 65 hours. The samples were analyzed by EC-UPLC to quantify the percentage of high molecular weight components (HMCS). The same method was used as described in example 4. The content of VMC in the samples after shaking is given in table. 22. ICH formation was least pronounced for the CD33cc-scFc construct in any prepared form.

Table 22

Generalized information on the content of VMC in CD33cc-hALB, -hFc and -scFc preparations exposed to stress (pH jump + 2H 37°C), determined using SEC-UPLC

Design hALB hFc scFc Ready form K60RTrT G40MSuT K60RTrT G40MSuT K60RTrT G40MSUT %vmk 65 h, 500 rpm 2.1 0.8 2.3 0, 4 1.3 0.2

Example 13.

The CD33cc-hALB, -hFc and -scFc constructs, prepared as described in Example 4, were exposed to visible and UVA light (photostress). In all preparations, the total protein concentration was 1 mg/ml. Protein solutions were filtered through a 0.22 μm pore size filter and poured into 0.5 ml type I glass vials. The CD33cc-hALB and -scFc constructs were subjected to two different tests involving 0.2 Ml visible light/25 Wh/ m ² UVA light and 1.2 Mlx visible light/173 Wh/m ² respectively. The CD33cc-hFc construct was subjected to two different tests involving 0.2 Mlx of visible light without UVA light and 1.2 Mlx of visible light/30 Wh/m ² UVA light, respectively. The temperature in the chamber was set to 25°C. After exposure to light, samples were analyzed by ECLC (Table 23) and peptide mapping (Table 24). The above methods were carried out in accordance with the procedures described in example 4. Despite the higher intensity of UVA light applied to the CD33cc-scFc construct, this construct was stable against ICH formation. In contrast, the CD33cc-hFc and CD33cc-hALB constructs showed an increase in the number of ICHs after the 2 test conditions.

Table 23 Generalized information on the content of VMC in CD33cc-hALB, -hFc and -scFc preparations, determined after exposure to light using SEC-UPLC

Design hALB hFc scFc Ready form K60RTrT G40MSUT K60RTrT G40MSUT K60RTrT G40MSUT %vmk That 1.5 0.3 2.7 0.3 1.3 0, 3 Test 1 1. 8 ¹ 0. z ¹ 2. 5 ² 0. z ² 1. 4 ¹ 0. з ¹ ' Test 2 4.6 ³⁾ 1.1 ³ > 6, 0 ⁴⁾ 0.7 ⁴⁾ 1.5 ³⁾ o, s ³⁾

1) 0.2 Mlk of visible light/25 Wh/ ^m2 UVA light, ²⁾ 0.2 Mlk of visible light without UVA light, ³⁾ 1.2 Mlk of visible light/173 W*h/ ^m2 , ⁴⁾ 1.2 mlk of visible light/30 Wh/ ^m2 .

Overall, chemical modifications following light exposure were least pronounced for the CD33cc-scFc construct. In particular, CDR deamidation was more pronounced in the CD3cc-hALB and CD33cc-hFc constructs. Compared to Fc-based constructs, the CD33cc-scFc construct was found to be less susceptible to chemical modifications of the Fc moiety, although the scFc construct was exposed to higher doses of UVA light than the hFc construct. In table 24 also lists the most common chemical modifications to the albumin portion of the CD33cc-hALB construct, demonstrating that the half-life extending portion of this construct was more chemically degraded than the Fc portions of the CD33cc-hFc and -scFc constructs.

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Table 24

Summary of chemical modifications in CD33cc-hALB, -hFc and -scFc preparations determined after light exposure using peptide mapping

Design hALB hFc scFc Finished form K60RTrT G40MSUT K60RTrT G40MSUT K60RTrT G40MSUT %M34 oxidation (CDR) THAT 10 1.8 1.0 1.4 1.7 19 Test 1 1.5 ¹¹ n. And. 0.7 ²⁾ 4.2 ²⁾ 1.4 ¹¹ 1.2 ¹¹ Test 2 1.7 ³⁾ n. And. 1.1 ⁴ > 4.2 ⁴ > 1.3 ³ > 1.7 ³ > %D103 isomerization [(CDR) THAT 0.8 0.8 0.8 0.8 0.6 0.6 Test 1 0.8 ¹ ' n. And. 0.9 ²⁾ 0.9 ² > 0.8 ¹ ' 1, O ¹ ' Test 2 1.1 ³ > n. And. 1.2 ⁴ > 1.4 ⁴ > 1.0 ³ > 1.3 ³ > %M2 90 oxidation (CDR) THAT 0.7 1.4 0.8 1 1.3 14 Test 1 1, I ¹ ' n. And. 0.5 ² > 3.3 ² > 1, O ¹ ' 0.9 ¹ ' Test 2 1.4 ³ > n. And. 1.1 ⁴ > 4.2 ⁴⁾ 1.0 ³⁾ 1.4 ³ > %N359 deamidation (CDR) THAT 5.8 11.4 5.3 6, 3 oh 4 0.5 Test 1 10.8 ¹ ' n. And. 4.5 ²⁾ 5.6 ² > 0.4 ¹ ' 0.2 ¹ ' Test 2 12.4 ³⁾ n. And. 10.3 ⁴ > 3.6 ⁴ > 0, 6 ³ > 0.2 ³ > %N362 deamidation (CDR) THAT 5.4 8.7 z, 9 4.0 0.2 0, 3 Test 1 8.8 ¹ ' n. And. 3.4 ²⁾ 3.5 ² > 0, Z ¹ ' 0, Z ¹ ' Test 2 9.8 ³ > n. And. 6, 4 ⁴ > 2.3 ⁴⁾ 0.5 ³⁾ 0, ³⁾ %D510 isomerization] 4 (Fc) THAT n. P. n. P. 0.4 0.4 0.5 oh 4 Test 1 n. P. n. P. 0.4 ²⁾ 0.6 ² > 0, b ¹ ' 0.5 ⁴⁾ Test 2 n. P. n. P. 0.7 ⁴ > 0.7 ⁴ > 0.7 ³ > 0.7 ³ > %M541 ( oxidation (Fc) THAT n. P. n. P. 2.8 3 3.7 4, 1 Test 1 n. P. n. P. 5, O ² ' 0.7 ² > 3.8 ¹ ' 3.8 ¹ ' Test 2 n. P. n. P. 17.5 ⁴⁾ 18.4 ⁴⁾ 4.8 ³⁾ 5.5 ³ > %N614 deamidation (Fc) THAT n. P. n. P. 1.2 1.2 1.6 1.5

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Test 1 n. P. n. P. 1.3 ² > 1.7 ² > 2.8 ¹ ' 2.2 ¹ ' Test 2 n. P. n. P. 6, 1 ⁴ > 1, 9 ⁴ > 1.9 ³ > 2, Z ³ > %N673 deamidation (Fc) THAT n. P. n. P. 0.3 0.3 0, 0 0, 0 Test 1 n. P. n. P. 0.5 ² > 0.6 ²⁾ 0.5 ¹ ' 0.6 ¹ ' Test 2 n. P. n. P. 0.5 ⁴ > 0, 6 ⁴ > 0.5 ³ > 1.5 ³ > %M717 oxidation (Fc) THAT n. P. n. P. 2.1 2.4 2.5 2.8 Test 1 n. P. n. P. 4.1 ² > 7.3 ² > 2.2 ⁴⁾ 2.3 ⁴⁾ Test 2 n. P. n. P. 13.7 ⁴ > 13.5 ⁴ > 2.8 ³⁾ 3.8 ³ > %M5 98 oxidation (hALB) THAT 10 n. And. n. P. n. P. n. P. n. P. Test 1 2, Z ¹ ' n. And. n. P. n. P. n. P. n. P. Test 2 6.4 ³ > n. And. n. P. n. P. n. P. n. P. %M8 0 9 oxidation (hALB) THAT 18 n. And. n. P. n. P. n. P. n. P. Test 1 3.5 ¹ ' n. And. n. P. n. P. n. P. n. P. Test 2 8, Z ³ > n. And. n. P. n. P. n. P. n. P. %M840 oxidation (hALB) THAT 12.8 n. And. n. P. n. P. n. P. n. P. Test 1 32, O ¹ ' n. And. n. P. n. P. n. P. n. P. Test 2 61.7 n. And. n. P. n. P. n. P. n. P. %K1036 glycation (hALB) THAT 10.1 n. And. n. P. n. P. n. P. n. P. Test 1 10.2 ¹ ' n. And. n. P. n. P. n. P. n. P. Test 2 9, 9 ³⁾ n. And. n. P. n. P. n. P. n. P.

1) 0.2 Mlk of visible light/25 Wh/ ^m2 UVA light, ²⁾ 0.2 Mlk of visible light without UVA light, ³⁾ 1.2 Mlk of visible light/173 W*h/ ^m2 , ⁴⁾ 1.2 mlk of visible light/30 Wh/ ^m2 .

Example 14.

Various BiTE® antibody constructs designed to target EGFRvIII were studied including EGFRvIII without half-life extension (non-HLE, canonical), EGFRvIII-hALB and EGFRvIII-scFc. The target protein concentration was 1.0 mg/mL for hALB and scFc and 0.4 mg/mL for the non-HLE version. The prepared BiTE® antibody constructs were poured up to 1 ml into Type I glass vials, which were sealed with butyl rubber stoppers and crimped with aluminum caps. The filled vials were incubated at -20°C and 37°C (without and with 25 ppm silicon, which is known to induce protein aggregation) for 4 weeks. The above structures were also exposed to light (1.2 Ml visible light/173 Wh/m ² UVA light). In case of light stress, the chamber temperature was set to 25°C. Samples stored at -70°C served as controls (T0).

The above samples were analyzed in duplicate by size exclusion ultra-high performance chromatography (SEC-UPLC) to quantify the percentage of high molecular weight components (HMCS). EC-UPLC was performed on an Aquity H-Class UPLC system (Waters) using a 150 mm Acquity UPLC BEH200 SEC column (Waters). The column temperature was set to 25°C. Separation of size variants was ensured using the isocratic method with a flow rate of 0.4 ml/min. The mobile phase consisted of 100 mM sodium phosphate, 250 mM NaCl, pH 6.8. Analysis time was 6.0 min overall. Samples were kept at 8°C in an autosampler until analysis. A total amount of protein of 3 μg was injected. To avoid contamination, an intermediate injection of 40% ACN was performed after each sample. Detection was based on fluorescence (excitation at 280 nm, emission at 325 nm). Peak integration was performed using Empower® software. The relative area under the ICH curve is presented (Table 25).

Among unstressed samples, ICHs were least expressed for the scFc construct. VMC formation was observed exclusively during 4-week storage at -20°C. The HMW content under these conditions increased in the following order: scFc < hALB < non-HLE.

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Table 25

Generalized information on the content of VMC in stressed and non-stressed (T0) preparations of EGFRvIII-non HLE, -hALB and -scFc, determined using EC-UPLC

Design He-HLE (canonical) hALB scFc THAT 1.3% 1.3% 1.0% 4n -20°С 4.6% 18% 1.6% 4n 37°С 0.9% 0.6% 0.5% 4n 37°C (25 ppm silicon) 1.1% 0.8% 0.8% Exposure to light 1.0% 0.9% 0.5%

In addition, thermally stressed samples in the absence and presence of silicon were assessed for particles invisible to the naked eye by microfluidic imaging (MFI) using Flowcam from Fluid Imaging Technologies, Inc. The device was equipped with an FC80FV flow cell. Tenfold optical magnification was used. The applicability of the system was confirmed using particle-free water. An automatic image acquisition speed of 20 frames per second was used. The shadow and highlight thresholds were set to 25 and 20 pixels, respectively. The total sample volume for one measurement was 0.25 ml. Sample measurements were carried out in triplicates. Before each triplicate, the system was washed with 0.5 ml of the corresponding sample solutions. At the beginning and between each triplicate, a wash with 1.0 ml of particle-free water was performed. Data evaluation was performed using Visual Spreadsheet software. Sample measurements were carried out in triplicates. The results are shown in table. 26.

Heat stress resulted in the formation of particles invisible to the naked eye in preparations containing non-HLE and hALB constructs. The scFc construct, on the contrary, remained stable. The addition of silicon did not stimulate the formation of particles invisible to the naked eye, regardless of the nature of the BiTE® antibody construct.

Table 26

Evaluation of particles invisible to the naked eye using the IMF method in EGFRvIII-non-HLE (canonical), -hALB and -scFc preparations after heat stress in the absence and presence of silicon

Design I He-HLE (canonical) hALB scFc Particle size [µm] > 2 > 5 10 25 > 2 > 5 10 25 > 2 > 5 10 25 THAT 146 35 12 0 281 71 35 0 298 150 33 0 4n 37°С 410 163 23 0 742 225 eleven 0 110 44 0 0 4n 37°C (25ppm silicon) 69 35 eleven 0 272 91 34 0 146 55 eleven 0

Samples that were subjected to heat stress were also analyzed by weak cation exchange (SCE) chromatography to quantify charge variant content using an Aquity H-class UPLC from Waters. A 4.6 x 100 mm Protein-Pak Hi Res CM 7im column (Waters, cat. no. 186004929) was used. The column temperature was set to 30°C. The flow rate was set to 0.65 ml/min. The applied gradient was designed as follows (Table 27). The autosampler temperature was maintained at 2-8°C.

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Table 27

Gradient used for RMSD chromatography

Time [min:s] % A 20 mM sodium phosphate, pH 6.5 % IN 20 mM sodium phosphate, 250 mM sodium chloride, pH 6, 5 00:00 100 0 4:00 100 0 25:00 50 50 25:01 0 100 29:00 0 100 29:01 100 0 33:00 100 0

A total amount of protein of 3 μg was injected. Detection was based on fluorescence (excitation at 280 nm, emission at 325 nm). Peak integration was performed using Empower® software. The relative areas under the curves of the main peak, as well as for acidic and basic charge variants, are given in Table. 28.

Heat stress resulted in a decrease in the percentage attributable to the main peak, which must be due to the predominant formation of acidic charge variants. The decrease in the percentage of the main peak was least pronounced for the scFc construct (7.5%). Major charge variants were formed in both designs with prolonged half-life after light exposure. The increase in the number of major charge variants ranged from 5 to 6% in the hALB and scFc constructs.

Table 28

Assessment of charge variants by RMSD chromatography in EGFRvIII-non-HLE (canonical), -hALB and -scFc preparations after heat- and light-induced stress.

Design He-HLE (canonical) hALB scFc % % % % % % % % % Fraction basics sour basics basics sour basics basics sour basics Noah s nykh Noah s nykh Noah s nykh THAT 89, 9 3.6 6, 5 83.3 0.7 16.0 74.5 3.4 22.1 4n 37°С 79.3 11.1 9, 5 75, 6 9.8 14.6 67.0 11.2 21.8

In addition, sample purity was assessed in heat- and light-stressed samples using microfluidic sodium dodecyl sulfate capillary electrophoresis (SC-SDS) analysis based on a LabChip GXII system (Perkin Elmer). The denaturing sample solution consisted of Protein Express HT sample buffer (supplied by Perkin Elmer) supplemented with 34 mM dithiothreitol. Each sample was diluted 1:8 with a denaturing solution and heated to 70°C for 10 min along with the protein express ladder. 35 μL of water for injection (WFI) was added to 40 μl of denatured sample. 120 μL of VDI was added to 12 μL of ladder. The samples, ladder, protein express wash buffer, gel dye, and decolorizing solution were transferred to their respective reservoirs. Samples were electrokinetically loaded from a microtiter plate onto the chip, combining separation, staining, decolorization, and detection of protein and its size variants. The resulting electropherograms were evaluated and changes in purity were recorded. General information on the percentage purity recorded after stress is given in Table. 29 and compared with unstressed samples (T0).

Higher purity was observed for the hALB and scFc constructs compared to the non-HLE construct under all conditions. A slight decrease in purity compared to T0 was recorded for hALB and scFc constructs after heat and light stress. The reduction in purity after 4 weeks of storage at 37°C was an overall 8.4% for the hALB construct and 6.6% for the scFc construct. The reduction after light exposure was comparable for the hALB and scFc constructs.

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Table 29

Summary of percentage purities in stressed and unstressed (NS) preparations of EGFRvIII-He-HLE, -hALB and -scFc determined ________________using LabChip GXII (Caliper)________________

Design He-HLE (canonical) hALB scFc THAT 57.4 96, 0 92.2 4n 37°С 60.6 87, 6 85.6 Impact Sveta 61.5 90, 1 86.4

Example 15.

Various BiTE® antibody constructs were prepared to target DLL3 including DLL3-hALB and DLL3-scFc, respectively. The target protein concentration was 1.0 mg/mL for both designs. The prepared BiTE® antibody constructs were poured up to 1 ml into Type I glass vials, which were sealed with butyl rubber stoppers and crimped with aluminum caps. Filled vials were incubated at 37°C (DLL3-hALB) and 40°C (DLL3-scFc) for 4 weeks. Samples stored at -70°C served as control (CT). Samples were analyzed by EC-UPLC according to the method described in example 13. The results are shown in table. thirty.

The scFc construct showed a smaller reduction in monomer abundance (2.3%) after heat stress compared to the hALB construct (4.0%), although the incubation temperature was slightly higher.

Table 30 Summary of Percentage Monomeric Peak in Stressed and Nonstressed (ST) DLL3-hALB and -scFc Preparations Determined by SEC-UPLC

Design hALB scFc THAT 97.6% 99.8% 4w 93.6% 97.5%

Example 16.

Various BiTE® antibody constructs were prepared to target CD 19 including the CO19-X body and CD19-scFc. The concentration of the target protein was 1.0 mg/ml. The prepared BiTE® antibody constructs were poured up to 1 ml into Type I glass vials, which were sealed with butyl rubber stoppers and crimped with aluminum caps. Filled vials were incubated at 20 and 37°C for 4 weeks. In addition, all samples were exposed to 1.2 Mlx visible light and 173 Wh/ ^m2 UVA light. The temperature in the chamber was set to 25°C. Samples stored at -70°C served as control (CT). Samples stored at -20 and -37°C were analyzed by EC-UPLC according to the method described in Example 13. The results are shown in table. 31.

The scFc construct retained higher monomer content when stored for four weeks at -20 and 37°C, respectively, compared to the X-body.

Table 31 Summary of information on monomer content in stressed and unstressed (SS) preparations CP19X-body and -scFc, determined using SEC-UPLC

Design X-body scFc THAT 100.0 98.8 4n -20°С 97.1 97, 9 4n 37°С 94.5 95.7

In addition, unstressed samples were assessed for the presence of particles invisible to the naked eye using microfluidic imaging (MFI) using the method described in example 13. The results are shown in table. 32. The CD19-scFc preparation showed significantly lower amounts of particles invisible to the naked eye compared to the CD19-Xbody preparation. This applies to all included size fractions.

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Table 32

Evaluation of particles invisible to the naked eye by MPI in stress-free CD19-X-body and -scFc constructs

Design X-body scFc Particle size [µm] > 2 > 5 > 10 > 25 > 2 > 5 > 10 > 25 THAT 2648 688 192 32 160 64 43 eleven

Samples that were subjected to light stress were also analyzed by weak cation exchange (SCE) chromatography to quantify the percentage of charge variants using UPLC Aquity H-Class from Waters according to the method described in Example 13. Relative areas under the main peak curves , as well as for acidic and basic charge variants are given in table. 33.

The scFc construct showed increased stability after light exposure compared to the X-body, as indicated by a less pronounced reduction in the main peak, which was 1.4% overall compared to 5.5% for the X-body construct.

Table 33

Assessment of charge variants by RMSD chromatography in CD19-X-body and -scFc preparations after heat- and light-induced stress

Design X-body scFc Fraction % % % % % % basic sour main basic ki heard main THAT 51.4 30.3 18.3 83.5 1.3 15.2 Impact Sveta 45, 9 33.2 20, 9 82.1 1.2 16, 7

Example 17. Size exclusion chromatography of bispecific scFc variants.

Designs D9F, T2G, D3L, T7I and K6C (see FIG. 7) were examined for their behavior during size exclusion chromatography tests according to standard procedures. More specifically, a specified amount of 25 μg of each construct was analyzed (at 750 μl/min) in lysine citrate buffer (10 mM and 75 mM, pH7) on a Superdex 200 increase 10/300GL column at room temperature and the OD was recorded at 280 nm. The designs were then compared in terms of retention time. As a result, construct D9F exhibited significantly slower elution (Table 34) compared to T2G, D3L, T7I and K6C, indicating a difference in the structure/ordering of the Fc domains. This difference in retention time was most significant for the T7I construct containing unpaired cysteines in the hinge region and a CH2 and CH2CH3 linkage to CH3 (18.98 min and 18.62 min, a difference of 0.36 min). However, the difference in retention time of 0.16 min between D9F and T2G is significant given the corresponding retention time of the BSA control. The BSA control showed a retention time of 19.07 min for monomers and 16.82 min for dimers, showing a difference of 2.25 min in retention time for the doubled molecular weight case. Therefore, since the constructs have a structural difference only in the Fc portion, the difference in retention time of 0.16 min is significant. Overall, construct D9F exhibited the longest retention time, indicating the strongest binding. This finding suggests that D9F also has the longest half-life in vivo.

Table 34

Design Holding time in min D9F 18.98 T2G 18.82 D3L 18.78 K6S 18.77 T7I 18, 62 BCA monomer 19, 07 BSA dimer 16, 82

Example 18 Determination of binding to human FcRn by surface plasmon resonance (FCGRT/B2M).

Constructs D9F, T2G, D3L, T7I and K6C (Fig. 7) were each tested for their ability to bind to human FcRn in SPR (Biacore) experiments according to standard procedures. More specifically, CM5 sensor chips (GE Healthcare) immobilized 450-500 EO

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FCGRT/B2M (ACRO Biosystems) using Na acetate buffer, pH 4.5, and running buffer consisting of 200 mM HEPES, 150 mM NaCl, 3 mM EDTA, pH 6.0. The constructs were then injected in sequential runs at two concentrations of 250 nM and 125 nM, diluted in 200 mM HEPES, 150 mM NaCl, 3 mM EDTA, pH 6.0, and at 36°C. Association was carried out for 90 s at a flow rate of 30 μl/min, followed by a dissociation phase for 90 s at a flow rate of 30 μl/min in 200 mM HEPES, 150 mM NaCl, 3 mM EDTA, pH 6.0, at 36°C . Subsequent reduction was carried out for 10 s at 30 μl/min with 10 mM GEPES, 150 mM NaCl, 3 mM EDTA, pH 7.4.

Maximum binding during the injection phase was measured for all constructs in corresponding response units (RUs) equivalent to the increase in molecular weight on the FcRn-coated CM5 chip due to the presence of the bound construct. All constructs were measured in duplicate. The average duplicate detection values are shown in Fig. 8A and 8B respectively.

As a result, the D9F construct exhibited a significantly greater increase in mass on the FcRn-coated CM5 chip compared to T2G, D3L, T7I, and K6C, indicating greater binding affinity of D9F to human FcRn. This observation occurred for both concentrations of the respective constructs.

Binding to FcRn is mediated by the Fc moiety of the constructs. Stronger binding to human FcRn, as described in the literature, is indicative of a longer half-life in vivo due to higher intracellular retention of the corresponding protein and therefore reduced levels of degradation. For this reason, D9F's stronger binding to human FcRn compared to other constructs makes this molecule clearly superior as a scaffold for therapeutic molecules, allowing the drug candidate to remain in the patient longer and with less frequency of drug administration.

Example 19 Determination of binding to human FcRn by surface plasmon resonance (FCGRT/B2M).

The constructs D9F, T2G, D3L, T7I and K6C and the human IgG1-kappa antibody MT201 were each tested for their ability to bind to human FcRn in SPR (Biacore) experiments according to standard procedures. More specifically, CM5 sensor chips (GE Healthcare) were immobilized with approximately 350 FU of FCGRT/B2M (ACRO Biosystems) using Na acetate buffer, pH 4.5, and a running buffer consisting of 200 mM HEPES, 150 mM NaCl, 3 mM EDTA , pH 6.0. The constructs and human IgG1-kappa control (MT201) were then injected at a concentration of 125 nM, diluted in 200 mM GEPES, 150 mM NaCl, 3 mM EdTA, pH 6.0, and at 36°C. Association was carried out for 90 s at a flow rate of 30 μl/min, followed by a dissociation phase for 60 s at a flow rate of 30 μl/min in 200 mM HEPES, 150 mM NaCl, 3 mM EDTA, pH 6.0, at 36°C . Subsequent reduction was carried out for 10 s at 30 μl/min with 10 mM GEPES, 150 mM NaCl, 3 mM EDTA, pH 7.4.

Maximum binding during the injection phase was measured for all constructs in corresponding response units (RUs) equivalent to the increase in molecular weight on the FcRn-coated CM5 chip due to the presence of the bound construct. All constructs were measured in duplicate. In fig. Figure 9 shows the average duplicate detection values, including error bars indicating the standard deviation.

As a result, the D9F construct exhibited a significantly greater increase in mass on the FcRn-coated CM5 chip compared to T2G, D3L, T7I, and K6C, indicating greater binding affinity of D9F to human FcRn. The increase in mass on the FcRn-coated CM5 chip for D9F compares well with the increase in mass of the human IgG1-kappa control antibody MT201, indicating comparable binding of the D9F construct to human FcRn.

Binding to FcRn is mediated by the Fc portion of human IgG1 in the constructs. Stronger binding to human FcRn, as described in the literature, is indicative of a longer half-life in vivo due to higher intracellular retention of the corresponding protein and therefore reduced levels of degradation. For this reason, the stronger binding of D9F to the human FcRn range of the human IgG1-kappa antibody (MT201) compared to other constructs makes this molecule clearly superior as a basis for therapeutic molecules, ensuring a longer residence of the potential drug in the body of the patient, presumably in range of the full-length human IgG1 antibody, and a lower frequency of drug administration.

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Sequence table

Table 35

SEQ ID NO: Designation Format/ Source Subsequence 1 . Linker G4S GGGGS 2. Linker (G4S)2 GGGGSGGGGS 3. Linker (G4S)3 GGGGSGGGGSGGGGS 4 . Linker (G4S)4 GGGGSGGGGSGGGGSGGGGS 5. Linker (G4S)5 GGGGSGGGGSGGGGSGGGGSGGGGS 6. Linker GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (G4S)6 7. Linker (G4S)7 GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS GGGGS 8 . Linker (G4S)8 GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS GGGGSGGGGS 9. Peptide linker PGGGGS 10 . Peptide linker PGGDGS eleven . Peptide linker SGGGGS 12 . Peptide linker GGGG 13 . CD3s- connecting VL qtvvtqepsltvspggtvtltcgsstgavt sgnypnwvqqkpgqaprgliggtkflapgt parfsgsllggkaaltlsgvqpedeaeyyc vlwysnrwvfgggtkltvl 14 . CD3s- connecting VH evqlvesggglvqpggslrlscaasgftfn syamnwvrqapgkglewvarirskynnyat yyadsvkgrftisrddskntaylqmnslkt edtavyycvrhgnfgnsyvswwaywgqgtl vtvss 15. CD3s binding scFv evqlvesggglvqpggslrlscaasgftfn syamnwvrqapgkglewvarirskynnyat yyadsvkgrftisrddskntaylqmnslkt edtavyycvrhgnfgnsyvswwaywgqgtl vtvssggggsggggsggggsqtvvtqepsl tvspggtvtltcgsstgavtsgn ypnwvqq kpgqaprgliggtkflapgtparfsgsllg gkaaltlsgvqpedeaeyycvlwysnrwvf gggtkltvl 16. hexa- histidine I'm a mark HHHHHH 17. Fc-monomer- dkthtcppcpapellggpsvfIfppkpkdt

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1 +c/-g Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceegygstyrcvsvltvlh gdwlngkeykckvsnkalpapiektiskak ggprepgvytlppsreemtkngvsltclvk gfypsdiavewesnggpennykttppvlds dgsfflyskitvdksrwgggnvfscsvmhe al hnhytgkslslspgk 18 . Fc-monomer2 +c/-g/delGK dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceegygstyrcvsvltvlh gdwlngkeykckvsnkalpapiektiskak ggprepgvytlppsreemtkngvsltclvk gfypsdiavewesnggpennykttppvlds dgsfflyskitvdksrwgggnvfscsvmhe alhnhytgkslslsp 19. Fc-monomer- 3 -c/ + g dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpreegynstyrvvsvltvlh gdwlngkeykckvsnkalpapiektiskak ggprepgvytlppsreemtkngvsltclvk gfypsdiavewesnggpennykttppvlds d gsfflyskitvdksrwgggnvfscsvmhe alhnhytgkslslspgk 20. Fc-monomer- 4 -c/+g/delGK dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpreegynstyrvvsvltvlh gdwlngkeykckvsnkalpapiektiskak ggprepgvytlppsreemtkngvsltclvk gfypsdiavewesnggpennykttppvlds d gsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslsp 21. Fc-monomer- 5 -c/-g dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpreegygstyrvvsvltvlh gdwlngkeykckvsnkalpapiektiskak

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gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttppvlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslspgk 22. Fc-monomer6 -c/-g/delGK dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpreeqygstyrvvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttpp vlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslsp 23. Fc-monomer- 7 + c/ + g dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqynstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttpp vlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslspgk 24. Fc-monomer- 8 +c/+g/delGK dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqynstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttpp vlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslsp 25. scFc-1 dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttpp vlds dgsfflyskitvdksrwqqgnvfscsvmhe

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alhnhytqkslslspgkGGGGSGGGGSGGG GSGGGGSGGGGSGGGGSdkthtcppcpape llggpsvfIfppkpkdtImisrtpevtcvv vdvshedpevkfnwyvdgvevhnaktkpce eqygstyrcvsvltvlhqdwlngkeykckv snkalpapiektiskakgqprepqvytlpp sreem tknqvsltclvkgfypsdiavewes ngqpennykttppvldsdgsfflyskitvd ksrwqqgnvfscsvmhealhnhytqkslsl spgk 26. scFc-2 dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttpp vlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqks1slspGGGGSGGGGSGGGGS GGGGSGGGGSGGGGSdkthtcppcpape11 ggpsvfIfppkpkdtImisrtpevtcvvvd vshedpevkfnwyvdgvevhnaktkpceeq ygstyrcvsvltvlhqdwlngkey kckvsn kalpapiektiskakgqprepqvytlppsr eemtknqvsltclvkgfypsdiavewesng qpennykttppvldsdgsfflyskitvdks rwqqgnvfscsvmheaIhnhytqkslslsp 27. scFc-3 dkthtcppcpape11ggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpreeqynstyrvvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttpp vlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslspgkGGGGSGGGGSGGG GSGGGGSGGGGSGGGGSdkthtcppcpape

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llggpsvfIfppkpkdtlmisrtpevtcvv vdvshedpevkfnwyvdgvevhnaktkpre eqynstyrvvsvltvlhqdwlngkeykckv snkalpapiektiskakgqprepqvytlpp sreemtknqvsltclvkgfypsdiavewes ngqpennykttppvldsdgsfflyskitvd ksrwqqgnvfscsvmhealhnhytqkslsl spgk 28. scFc-4 dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpreeqynstyrvvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttppv lds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslspGGGGSGGGGSGGGGS GGGGSGGGGSGGGGSdkthtcppcpape11 ggpsvfIfppkpkdtImisrtpevtcvvvd vshedpevkfnwyvdgvevhnaktkpreeq ynstyrvvsvltvlhqdwlngkeykckv sn kalpapiektiskakgqprepqvytlppsr eemtknqvsltclvkgfypsdiavewesng qpennykttppvidsdgsfflyskitvdks rwqqgnvfscsvmheaIhnhytqkslslsp 29. scFc-5 dkthtcppcpape11ggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpreeqygstyrvvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennyktt ppvlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslspgkGGGGSGGGGSGGG GSGGGGSGGGGSGGGGSdkthtcppcpape llggpsvfIfppkpkdtlmisrtpevtcvv vdvshedpevkfnwyvdgvevhnaktkpre

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eqygstyrvvsvltvlhqdwlngkeykckv snkalpapiektiskakgqprepqvytlpp sreemtknqvsltclvkgfypsdiavewes ngqpennykttppvldsdgsfflyskitvd ksrwqqgnvfscsvmheaihnhytqkslsl spgk thirty. scFc-6 dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpreeqygstyrvvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttpp vlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqks1slspGGGGSGGGGSGGGGS GGGGSGGGGSGGGGSdkthtcppcpapell ggpsvfifppkpkdtlmisrtpevtcvvvd vshedpevkfnwyvdgvevhnaktkpreeq ygstyrvvsvltvlhqdwlngkeyk ckvsn kalpapiektiskakgqprepqvytlppsr eemtknqvsltclvkgfypsdiavewesng qpennykttppvldsdgsfflyskitvdks rwqqgnvfscsvmheaihnhytqkslslsp 31. scFc-7 dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqynstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttpp vlds dgsfflyskltvdksrwqqgnvfscsvmhe alhnhytqkslslspgkGGGGSGGGGSGGG GSGGGGSGGGGSGGGGSdkthtcppcpape llggpsvfifppkpkdtlmisrtpevtcvv vdvshedpevkfnwyvdgvevhnaktkpce eqynstyrcvsvltvlhqdwlngkeyk ckv snkalpapiektiskakgqprepqvytlpp

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sreemtknqvsltclvkgfypsdiavewes ngqpennykttppvldsdgsfflyskitvd ksrwqqgnvfscsvmhealhnhytqkslsl spgk 32. scFc-8 dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqynstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttpp vlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslspGGGGSGGGGSGGGGS GGGGSGGGGSGGGGSdkthtcppcpapell ggpsvfIfppkpkdtlmisrtpevtcvvvd vshedpevkfnwyvdgvevhnaktkpceeq ynstyrcvsvltvlhqdwlngkeykck vsn kalpapiektiskakgqprepqvytlppsr eemtknqvsltclvkgfypsdiavewesng qpennykttppvldsdgsfflyskitvdks rwqqgnvfscsvmhealhnhytqkslslsp 33. MSLN-HLE HeteroEc, chain 1 qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgintwlawyqqkpgkapkll i ygasglqsgvpsrfsgsgsgtdftltissl qpedfatyycqqaksfprtfgqgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs

- 75 043309

gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkitvlggggdkthtcppcpap ellggpsvfIfppkpkdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprep qvytlp psrkemtknqvsltclvkgfypsdiavewe sngqpennykttppvlksdgsfflyskitv dksrwqqgnvfscsvmhealhnhytqksls Ispgk 34. MSLN-HLE Hetero- EU, chain 2 dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennydttpp vlds dgsfflysdltvdksrwqqgnvfscsvmhe alhnhytqkslslspgk 35. MSLN-HLE hALBmerge Qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgintwlawyqqkpgkapklli ygasglqsgvpsrfsgsgsgtdftltissl qpedfatyycqqaksfprtfgqgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisyway w gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkitvlpggdgsdahksevahr

- 76 043309

fkdlgeenfkalvliafaqylqqcpfedhv klvnevtefaktevadesaencdkslhtIf gdklctvatlretygemadccakqeperne cfIqhkddnpnlprlvrpevdvmctafhdn eetfIkkylyeiarrhpyfyapellffakr ykaafteccqaadkaacllpkldelrdegk assak qrlkcaslqkfgerafkawavarls qrfpkaefaevsklvtdltkvhtecchgdl 1ecaddradlakyicenqdsissklkecce kpllekshciaevendempadlpslaadfv eskdvcknyaeakdvfIgmflyeyarrhpd ysvvlllrlaktyettlekccaaadphecy akvfdefkplveepqnlikq ncelfeqlge ykfqnallvrytkkvpqvstptlvevsrnl gkvgskcckhpeakrmpcaedylsvvlnql cvlhektpvsdrvtkccteslvnrrpcfsa levdetyvpkefnaetftfhadictlseke rqikkqtalvelvkhkpkatkeqlkavmdd faafvekcckaddketcfaeegkklva asq aalglhhhhhh 36. CDH19-HLEa X-body, chain 1 evqlvesggglvqpggslklscaasgftfn kyamnwvrqapgkglewvarirskynnyat yyadsvkdrftisrddskntaylqmnnlkt edtavyycvrhgnfgnsyisywaywgqgtl vtvssggggsggggssyeltqppsvsvspg qtasitcsgdrlgekytswyq qrpgqspll viyqdtkrpsgiperfsgsnsgntatltis gtqamdeadyycqawesstvvfgggtkltv lastkgpsvfplapsskstsggtaalgclv kdyfpepvtvswnsgaltsgvhtfpavlqs sglyslssvvtvpssslgtqtyicnvnhkp sntkvdkkvep kscdkthtcppcpapellg gpsvfIfppkpkdtlmisrtpevtcvvvdv shedpevkfnwyvdgvevhnaktkpceeqy gstyrcvsvltvlhqdwlngkeykckvsnk

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alpapiektiskakgqprepqvytlppsre emtknqvsltclvkgfypsdiavewesngq pennydttppvldsdgsfflysdltvdksr wqqgnvfscsvmhealhnhytqkslslspg to 37. CDH19-HLEb X-body, chain 2 qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsqtvvtqepsltvspg gtvtltcgsstgavts gnypnwvqqkpgqa prgliggtkflapgtparfsgsllggkaal tlsgvqpedeaeyycvlwysnrwvfgggtk Itvlgqpkaapsvtlfppsseelqankatl vclisdfypgavtvawkadsspvkagvett tpskqsnnkyaassylsltpeqwkshrsys cqvthegstvekt vaptecsdkthtcppcp apellggpsvfIfppkpkdtlmisrtpevt cvvvdvshedpevkfnwyvdgvevhnaktk pceeqygstyrcvsvltvlhqdwlngkeyk ckvsnkalpapiektiskakgqprepqvyt Ippsrkemtknqvsltclvkgfypsdiave wesngqpennykt tppvlksdgsfflyski tvdksrwqqgnvfscsvmhealhnhytqks Islspgk 38. CDH19-HLE HeteroEc, chain 1 qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdr lgekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv

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arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgggtlvtvssggggsggggsggg gsgtvvtgepsltvspggtvtltcgsstga vtsgnypnwvggkpggaprgliggtkflap gtparfsgsllggkaaltlsgvgpedeaey ycv lwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceegygstyrcvsvltvlhgdwln gkeykckvsnkalpapiektiskakggpre pgvytlppsrkemtkngvsltclvkg fyps diavewesnggpennykttppvlksdgsff lyskltvdksrwgggnvfscsvmhealhnh ytgkslslspgk 39. CDH19-HLE Hetero- EU, chain 2 dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceegygstyrcvsvltvlh gdwlngkeykckvsnkalpapiektiskak ggprepgvytlppsreemtkngvsltclvk gfypsdiavewesnggpennydttppvlds dgsfflysdltvdksrwgggnvfscsvmhe alhnhytgkslslspgk 40. CD33-HLE HeteroEc, chain 1 qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkgapggclewmgwintytgepty adkfggrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ssggggsggggsggggsdivmtgspdsltv s1gerttinckssgsvids stnknslawyg gkpggppklllswastresgipdrfsgsgs gtdftltidspgpedsatyycggsahfpit fgcgtrleiksggggsevglvesggglvgp ggslklscaasgftfnkyamnwvrgapgkg lewvarirskynnyatyyadsvkdrftisr ddskntaylgmnnlktedtavyycvrhgnf

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gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvlggggd kthtcppcpapellggpsv fIfppkpkdtl misrtpevtcvvvdvshedpevkfnwyvdg vevhnaktkpceeqygstyrcvsvltvlhq dwlngkeykckvsnkalpapiektiskakg qprepqvytlppsrkemtknqvsltclvkg fypsdiavewesngqpennykttppvlksd gsfflyskitvdksrwq qgnvfscsvmhea Ihnhytqkslslspgk 41. CD33-HLE Hetero- EU, chain 2 dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennydttpp vlds dgsfflysdltvdksrwqqgnvfscsvmhe alhnhytqkslslspgk 42. CD33-HLE scFc qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqclewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ssggggsggggsggggsdivmtqspdsltv s1gerttinckssq svidsstnknslawyq qkpgqppklllswastresgipdrfsgsgs gtdftltidspqpedsatyycqqsahfpit fgcgtrleiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddskntaylqmnnlktedtavyyc vrhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs

- 80 043309

stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvlggggd kthtcppcpapellggpsvfIfppkpkdtl misrtpevtcvvvdvshedpevkfnwyvdg vevhnaktkpceeqygsty rcvsvltvlhq dwlngkeykckvsnkalpapiektiskakg qprepqvytlppsreemtknqvsltclvkg fypsdiavewesngqpennykttppvldsd gsfflyskitvdksrwqqgnvfscsvmhea Ihnhytqkslslspgkggggsggggsgggg sggggsggggsggggsdkthtc ppcpapel IggpsvfIfppkpkdtlmisrtpevtcvvv dvshedpevkfnwyvdgvevhnaktkpcee qygstyrcvsvltvlhqdwlngkeykckvs nkalpapiektiskakgqprepqvytlpps reemtknqvsltclvkgfypsdiavewesn gqpennykttppvldsdgsffly skitvdk srwqqgnvfscsvmheaIhnhytqkslsls pgk 43. CD20-HLE scFc qvqlvqsgaevkkpgssvkvsckasgyafs yswinwvrqapgqglewmgrifpgdgdtdy ngkfkgrvtitadkststaymelsslrsed tavyycarnvfdgywlvywgqgtlvtvssg gggsggggsggggsdivmtqtplslpvtpg epasicrssksllhs ngitylywylqkpg qspqlliyqmsnlvsgvpdrfsgsgsgtdf tlkisrveaedvgvyycaqnlelpytfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedta vyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap

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gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapie ktiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtp evtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhe alhnhytqkslslspgk 44. CD33xI2C- scFc VH CDR1 nygmn 45. CD33xI2C- scFc VH CDR2 wintytgeptyadkfqg 46. CD33xI2C- scFc VH CDR3 wswsdgyyvyfdy 47. CD33xI2C- scFc VL CDR1 kssqsvldsstnknsla 48. CD33xI2C- scFc VL CDR2 wastes 49. CD33xI2C- scFc VL CDR3 qqsahfpit 50. CD33xI2C- scFc VH qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqglewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ss

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51. CD33xI2C- scFc VL divmtqspdsltvsIgerttlackssqsvl dsstnknslawyqqkpgqppklllswastr esgipdrfsgsgsgtdftltidspqpedsa tyycqqsahfpitfgqgtrleik 52. CD33xI2C- scFc scFv qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqglewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ssggggsggggsggggsdivmtqspdsltv s1gerttinckssq svldsstnknslawyq qkpgqppklllswastresgipdrfsgsgs gtdftltidspqpedsatyycqqsahfpit fgqgtrleik 53. CD33xI2C- scFc Bispecific molecule qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqglewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ssggggsggggsggggsdivmtqspdsltv sIgerttinckssq svldsstnknslawyq qkpgqppklllswastresgipdrfsgsgs gtdftltidspqpedsatyycqqsahfpit fgqgtrleiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddskntaylqmnnlktedtavyy cvrhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvl 54. CD33xI2C- scFc Bispecific HLE molecule qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqglewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ssggggsggggsggggsdivmtqspdsltv

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sigerttinckssqsvidsstnknslawyq qkpgqppklllswastresgipdrfsgsgs gtdftltidspqpedsatyycqqsahfpit fgqgtrleiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddsknta ylqmnnlktedtavyycvrhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvlgg ggd kthtcppcpapellggpsvf1fppkpkdtl misrtpevtcvvvdvshedpevkfnwyvdg vevhnaktkpceeqygstyrcvsvltvlhq dwlngkeykckvsnkalpapiektiskakg qprepqvytlppsreemtknqvsltclvkg fypsdiavewesngqpennykttppv ldsd gsfflyskitvdksrwqqgnvfscsvmhea Ihnhytqkslslspgkggggsggggsgggg sggggsggggsggggsdkthtcppcpapel Iggpsvf1fppkpkdtlmisrtpevtcvvv dvshedpevkfnwyvdgvevhnaktkpcee qygstyrcvsvltvlhqd wlngkeykckvs nkalpapiektiskakgqprepqvytlpps reemtknqvsltclvkgfypsdiavewesn gqpennykttppvldsdgsfflyskitvdk srwqqgnvfscsvmhealhnhytqkslsls pgk 55. CD33xI2CscFc_delGK Bispecific HLE molecule qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqglewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ssggggsggggsggggsdivmtqspdsltv sigerttinckssqs vidsstnknslawyq

- 84 043309

qkpgqppklllswastresgipdrfsgsgs gtdftltidspqpedsatyycqqsahfpit fgqgtrleiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddskntaylqmnnlktedtavyycvrhgnf gnsyis ywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvlggggd kthtcppcpape11ggpsvfIfppk pkdt1 misrtpevtcvvvdvshedpevkfnwyvdg vevhnaktkpceeqygstyrcvsvltvlhq dwlngkeykckvsnkalpapiektiskakg qprepqvytlppsreemtknqvsltclvkg fypsdiavewesngqpennykttppvldsd gs fflyskitvdksrwqqgnv fscsvmhea ihnhytqkslslspggggsggggsggggsg gggsggggsggggsdkthtcppcpapellg gpsvfIfppkpkdtImisrtpevtcvvvdv shedpevkfnwyvdgvevhnaktkpceeqy gstyrcvsvltvlhqdwlngkeykckvsnk alpapiektiskakgqpre pqvytlppsre emtknqvsltclvkgfypsdiavewesngq pennykttppvidsdgsfflyskitvdksr wqqgnvfscsvmhealhnhytqkslslspg to 56. CD33_CCxI2C -scFc VH qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqclewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ss 57. CD33_CCxI2C -scFc VL divmtqspdsltvslgerttinckssqsvl dsstnknslawyqqkpgqppklllswastr

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esgipdrfsgsgsgtdftltidspqpedsa tyycqqsahfpitfgcgtrleik 58. CD33_CCxI2C -scFc scFv qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqclewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ssggggsggggsggggsdivmtqspdsltv slgerttinckssqsv ldsstnknslawyq qkpgqppklllswastresgipdrfsgsgs gtdftltidspqpedsatyycqqsahfpit fgcgtrleik 59. CD33_CCxI2C Bispecific molecule qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqclewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ssggggsggggsggggsdivmtqspdsltv slgerttinckssqsv ldsstnknslawyq qkpgqppklllswastresgipdrfsgsgs gtdftltidspqpedsatyycqqsahfpit fgcgtrleiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddskntaylqmnnlktedtavyycv rhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvl 60. CD33_CCxI2C -scFc Bispecific HLE molecule qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqclewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ssggggsggggsggggsdivmtqspdsltv slgerttinckssqsv ldsstnknslawyq qkpgqppklllswastresgipdrfsgsgs

- 86 043309

gtdftltidspqpedsatyycqqsahfpit fgcgtrleiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddskntaylqmnnlktedtavyycvrhgnf gnsyisywaywgqgtlvtvssggggsgggg sgggg sqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvlggggd kthtcppcpapellggpsvfIfppkpkdt1 misrtpevtcvvvdvshedpevkfn wyvdg vevhnaktkpceeqygstyrcvsvltvlhq dwlngkeykckvsnkalpapiektiskakg qprepqvytlppsreemtknqvsltclvkg fypsdiavewesngqpennykttppvldsd gsfflyskitvdksrwqqgnvfscsvmhea Ihnhytqkslslspgkggggsggggs gggg sggggsggggsggggsdkthtcppcpapel IggpsvfIfppkpkdtlmisrtpevtcvvv dvshedpevkfnwyvdgvevhnaktkpcee qygstyrcvsvltvlhqdwlngkeykckvs nkalpapiektiskakgqprepqvytlpps reemtknqvsltclvkgfypsdiave wesn gqpennykttppvldsdgsfflyskitvdk srwqqgnvfscsvmhealhnhytqkslsls pgk 61. CD33_CCxI2C -scFc_delGK Bispecific HLE molecule qvqlvqsgaevkkpgesvkvsckasgytft nygmnwvkqapgqclewmgwintytgepty adkfqgrvtmttdtststaymeirnlggdd tavyycarwswsdgyyvyfdywgqgtsvtv ssggggsggggsggggsdivmtqspdsltv s1gerttinckssq svidsstnknslawyq qkpgqppklllswastresgipdrfsgsgs gtdftltidspqpedsatyycqqsahfpit

- 87 043309

fgcgtrleiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddskntaylqmnnlktedtavyycvrhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvlggggd kthtcppcpape11ggpsvfIfppkpkdt1 misrtpevtcvvvdvshedpevkfnwyvdg vevhnaktkpceeqygsty rcvsvltvlhq dwlngkeykckvsnkalpapiektiskakg qprepqvytlppsreemtknqvsltclvkg fypsdiavewesngqpennykttppvldsd gsfflyskitvdksrwqqgnvfscsvmhea Ihnhytqkslslspggggsggggsggggsg gggsggggsggggsdkthtcpp cpapellg gpsvfIfppkpkdtImisrtpevtcvvvdv shedpevkfnwyvdgvevhnaktkpceeqy gstyrcvsvltvlhqdwlngkeykckvsnk alpapiektiskakgqprepqvytlppsre emtknqvsltclvkgfypsdiavewesngq pennykttppvidsdgsfflyski tvdksr wqqgnvfscsvmheaIhnhytqkslslspg to 62. EGFRvIIIxCD 3-scFc VH CDR1 nygmh 63. EGFRvIIIxCD 3-scFc VH CDR2 viwydgsdkyyadsvrg 64. EGFRvIIIxCD 3-scFc VH CDR3 dgydiltgnprdfdy 65. EGFRvIIIxCD 3-scFc VL CDR1 rssqslvhsdgntyls 66. EGFRvIIIxCD VL CDR2 risrrfs

- 88 043309

3-scFc 67. EGFRvIIIxCD 3-scFc VL CDR3 mqsthvprt 68. EGFRvIIIxCD 3-scFc VH qvqlvesgggvvqsgrslrlscaasgftfr nygmhwvrqapgkglewvaviwydgsdkyy adsvrgrftisrdnskntlylqmnslraed tavyycardgydiltgnprdfdywgqgtlv tvss 69. EGFRvIIIxCD 3-scFc VL dtvmtqtplsshvtlgqpasiscrssqslv hsdgntylswlqqrpgqpprlliyrisrrf sgvpdrfsgsgagtdftleisrveaedvgv yycmqsthvprtfgqgtkveik 70. EGFRvIIIxCD 3-scFc scFv qvqlvesgggvvqsgrslrlscaasgftfr nygmhwvrqapgkglewvaviwydgsdkyy adsvrgrftisrdnskntlylqmnslraed tavyycardgydiltgnprdfdywgqgtlv tvssggggsggggsggggsdtvmtqtplss hvtlgqpasiscrssqslvhsdgn tylswl qqrpgqpprlliyrisrrfsgvpdrfsgsg agtdftleisrveaedvgvyycmqsthvpr tfgqgtkveik 71. EGFRvIIIxCD 3-scFc Bispecific molecule qvqlvesgggvvqsgrslrlscaasgftfr nygmhwvrqapgkglewvaviwydgsdkyy adsvrgrftisrdnskntlylqmnslraed tavyycardgydiltgnprdfdywgqgtlv tvssggggsggggsggggsdtvmtqtplss hvtlgqpasiscrssqslvhsdgn tylswl qqrpgqpprlliyrisrrfsgvpdrfsgsg agtdftleisrveaedvgvyycmqsthvpr tfgqgtkveiksggggsevqlvesggglvq pggslklscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlktedtavyy cvrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg

-89043309

sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsgsllggkaaltlsgvqpe deaeyycvlwysnrwvfgggtkitvl 72. EGFRvIIIxCD 3-scFc Bispecific HLE molecule qvqlvesgggvvqsgrsIriscaasgftfr nygmhwvrqapgkglewvaviwydgsdkyy adsvrgrftisrdnskntlylqmnslraed tavyycardgydiltgnprdfdywgqgtlv tvssggggsggggsggggsdtvmtqtplss hvtlgqpasiscrssqslvhsdgnty lswl qqrpgqpprlliyrisrrfsgvpdrfsgsg agtdftleisrveaedvgvyycmqsthvpr tfgqgtkveiksggggsevqlvesggglvq pggslklscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlktedtavyyc vrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsgsllggkaaltlsgvqpe deaeyycvlwysnrwvfgggtkitvlgggg dkthtcppcp apellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttppvlds dgsfflyskit vdksrwqqgnvfscsvmhe alhnhytqkslslspgkggggsggggsggg gsggggsggggsggggsdkthtcppcpape llggpsvfIfppkpkdtlmisrtpevtcvv vdvshedpevkfnwyvdgvevhnaktkpce eqygstyrcvsvltvlhqdwlngkeykckv snkalpapie ktiskakgqprepqvytlpp sreemtknqvsItclvkgfypsdiavewes ngqpennykttppvldsdgsfflyskitvd

- 90 043309

ksrwqqgnvfscsvmhealhnhytqkslsl spgk 73. EGFRvIIIxCD 3- scFc_delGK Bispecific HLE molecule qvqlvesgggvvqsgrslrlscaasgftfr nygmhwvrqapgkglewvaviwydgsdkyy adsvrgrftisrdnskntlylqmnslraed tavyycardgydiltgnprdfdywgqgtlv tvssggggsggggsggggsdtvmtqtplss hvtlgqpasiscrssqslvhsdgn tylswl qqrpgqpprlliyrisrrfsgvpdrfsgsg agtdftleisrveaedvgvyycmqsthvpr tfgqgtkveiksggggsevqlvesggglvq pggslklscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlktedtavyy cvrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsgsllggkaaltlsgvqpe deaeyycvlwysnrwvfgggtkltvlgggg dkthtcppc papellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttppvlds dgsfflyski tvdksrwqqgnvfscsvmhe alhnhytqkslslspggggsggggsggggs ggggsggggsggggsdkthtcppcpapell ggpsvfIfppkpkdtImisrtpevtcvvvd vshedpevkfnwyvdgvevhnaktkpceeq ygstyrcvsvltvlhqdwlngkeykckvsn kal papiektiskakgqprepqvytlppsr eemtknqvsltclvkgfypsdiavewesng qpennykttppvldsdgsfflyskitvdks rwqqgnvfscsvmhealhnhytqkslslsp

- 91 043309

gk 74. EGFRvIII_CC xCD3-scFc VH qvqlvesgggvvqsgrslrlscaasgftfr nygmhwvrqapgkclewvaviwydgsdkyy adsvrgrftisrdnskntlylqmnslraed tavyycardgydiltgnprdfdywgqgtlv tvss 75. EGFRvIII_CC xCD3-scFc VL dtvmtqtplsshvtlgqpasiscrssqslv hsdgntylswlqqrpgqpprlliyrisrrf sgvpdrfsgsgagtdftleisrveaedvgv yycmqsthvprtfgcgtkveik 76. EGFRvIII_CC xCD3-scFc scFv qvqlvesgggvvqsgrslrlscaasgftfr nygmhwvrqapgkclewvaviwydgsdkyy adsvrgrftisrdnskntlylqmnslraed tavyycardgydiltgnprdfdywgqgtlv tvssggggsggggsggggsdtvmtqtplss hvtlgqpasiscrssqslvhsdgn tylswl qqrpgqpprlliyrisrrfsgvpdrfsgsg agtdftleisrveaedvgvyycmqsthvpr tfgcgtkveik 77. EGFRvIII_CC xCD3-scFc Bispecific HLE molecule qvqlvesgggvvqsgrslrlscaasgftfr nygmhwvrqapgkclewvaviwydgsdkyy adsvrgrftisrdnskntlylqmnslraed tavyycardgydiltgnprdfdywgqgtlv tvssggggsggggsggggsdtvmtqtplss hvtlgqpasiscrssqslvhsdgn tylswl qqrpgqpprlliyrisrrfsgvpdrfsgsg agtdftleisrveaedvgvyycmqsthvpr tfgcgtkveiksggggsevqlvesggglvq pggslklscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlktedtavyy cvrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsgsllggkaaltlsgvqpe

- 92 043309

deaeyycvlwysnrwvfgggtkltvl 78. EGFRvIII_CC xCD3-scFc Bispecific HLE molecule qvqlvesgggvvqsgrslrlscaasgftfr nygmhwvrqapgkclewvaviwydgsdkyy adsvrgrftisrdnskntlylqmnslraed tavyycardgydiltgnprdfdywgqgtlv tvssggggsggggsggggsdtvmtqtplss hvtlgqpasiscrssqslvhsdgn tylswl qqrpgqpprlliyrisrrfsgvpdrfsgsg agtdftleisrveaedvgvyycmqsthvpr tfgcgtkveiksggggsevqlvesggglvq pggslklscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlktedtavyy cvrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsgsllggkaaltlsgvqpe deaeyycvlwysnrwvfgggtkltvlgggg dkthtcppc papellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttppvlds dgsfflyski tvdksrwqqgnvfscsvmhe alhnhytqkslslspgkggggsggggsggg gsggggsggggsggggsdkthtcppcpape llggpsvfIfppkpkdtlmisrtpevtcvv vdvshedpevkfnwyvdgvevhnaktkpce eqygstyrcvsvltvlhqdwlngkeykckv snkalpa piektiskakgqprepqvytlpp sreemtknqvsltclvkgfypsdiavewes ngqpennykttppvidsdgsfflyskitvd ksrwqqgnvfscsvmheaIhnhytqkslsl spgk

- 93 043309

79. EGFRvIII_CC xCD3scFc_delGK bispecifically ical molecule qvqlvesgggvvqsgrslrlscaasgftfr nygmhwvrgapgkclewvaviwydgsdkyy adsvrgrftisrdnskntlylgmnslraed tavyycardgydiltgnprdfdywgqgtlv tvssggggsggggsggggsdtvmtgtplss hvtlggpasiscrssgslvhsdgntyls wl qqrpgqpprlliyrisrrfsgvpdrfsgsg agtdftleisrveaedvgvyycmgsthvpr tfgcgtkveiksggggsevglvesggglvq pggslklscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylgmnnlktedtavyycvr hgn fgnsyisywaywgggtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsgsllggkaaltlsgvgpe deaeyycvlwysnrwvfgggtkltvlgggg dkthtcppcpapellgg psvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceegygstyrcvsvltvlh gdwlngkeykckvsnkalpapiektiskak ggprepgvytlppsreemtkngvsltclvk gfypsdiavewesnggpennykttppvlds dgsfflyskitvdksrwgg gnvfscsvmhe alhnhytgkslslspggggsggggsggggs ggggsggggsggggsdkthtcppcpapell ggpsvfifppkpkdtimisrtpevtcvvvd vshedpevkfnwyvdgvevhnaktkpceeq ygstyrcvsvltvlhgdwlngkeykckvsn kalpapiektiskakgqprep gvytlppsr eemtkngvsltclvkgfypsdiavewesng gpennykttppvldsdgsfflyskitvdks rwgqgnvfscsvmhealhnhytgkslslsp gk 80. MS_lxCD3- VH CDR1 dyymt

- 94 043309

scFc 81. MS_lxCD3scFc VH CDR2 yisssgstiyyadsvkg 82. MS_lxCD3scFc VH CDR3 drnshfdy 83. MS_lxCD3scFc VL CDR1 rasqgintwla 84. MS_lxCD3scFc VL CDR2 gasglqs 85. MS_lxCD3scFc VL CDR3 qqaksfprt 86. MS_lxCD3scFc VH qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvss 87. MS_lxCD3scFc VL diqmtqspssvsasvgdrvtitcrasqgin twlawyqqkpgkapklliygasglqsgvps rfsgsgsgtdftltisslqpedfatyycqq aksfprtfgqgtkveik 88. MS_lxCD3scFc scFv qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgintwlawyqqkpgkapkll i ygasglqsgvpsrfsgsgsgtdftltissl qpedfatyycqqaksfprtfgqgtkveik 89. MS_lxCD3scFc Bispecific molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgintwlawyqqkpgkapkll i ygasglqsgvpsrfsgsgsgtdftltissl qpedfatyycqqaksfprtfgqgtkveiks

- 95 043309

ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisywayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvl 90. MS_lxCD3scFc Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgintwlawyqqkpgkapkll i ygasglqsgvpsrfsgsgsgtdftltissl qpedfatyycqqaksfprtfgqgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap ellggpsvfIfppkp kdtImisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsltclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgnvfsc svmhealhnhytqksls Ispgkggggsggggsggggsggggsggggs ggggsdkthtcppcpape11ggpsvfIfpp

- 96 043309

kpkdtlmisrtpevtcvvvdvshedpevkf nwyvdgvevhnaktkpceeqygstyrcvsv Itvlhqdwlngkeykckvsnkalpapiekt iskakgqprepqvytlppsreemtknqvsl tclvkgfypsdiavewesngqpennykttp pvldsdgsfflyskitvdksrwqq gnvfsc svmhealhnhytqkslslspgk 91. MS_lxCD3scFc_delGK Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgintwlawyqqkpgkapkll i ygasglqsgvpsrfsgsgsgtdftltissl qpedfatyycqqaksfprtfgqgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap elIggpsvfIfppk pkdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsltclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgnvf scsvmhealhnhytqksls Ispggggsggggsggggsggggsggggsgg ggsdkthtcppcpapelIggpsvfIfppkp kdtlmisrtpevtcvvvdvshedpevkfnw yvdgvevhnaktkpceeqygstyrcvsvlt

- 97 043309

vlhqdwlngkeykckvsnkalpapiektis kakgqprepqvytlppsreemtknqvsltc Ivkgfypsdiavewesngqpennykttppv Idsdgsfflyskitvdksrwqqgnvfscsv mhealhnhytqkslslspgk 92. MS_l_CCxCD ³ -scFc VH qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkclewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvss 93. MS_l_CCxCD ³ -scFc VL diqmtqspssvsasvgdrvtitcrasqgin twlawyqqkpgkapklliygasglqsgvps rfsgsgsgtdftltisslqpedfatyycqq aksfprtfgcgtkveik 94. MS_l_CCxCD ³ -scFc scFv qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkclewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgintwlawyqqkpgkapkll i ygasglqsgvpsrfsgsgsgtdftltissl qpedfatyycqqaksfprtfgcgtkveik 95. MS_l_CCxCD ³ -scFc Bispecific molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkclewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgintwlawyqqkpgkapkll i ygasglqsgvpsrfsgsgsgtdftltissl qpedfatyycqqaksfprtfgcgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp

- 98 043309

nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvl 96. -scFc Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkclewlsyisssgstiyy adsvkgrftisrdnaknslfiqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgintwlawyqqkpgkapkll i ygasglqsgvpsrfsgsgsgtdftltissl qpedfatyycqqaksfprtfgcgtkveiks ggggsevqlvesggglvqpggsIkiscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyis ywayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap ellggpsvfifppk pkdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsltclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgnvf scsvmhealhnhytqksis ispgkggggsggggsggggsggggsggggs ggggsdkthtcppcpapellggpsvfIfpp kpkdtlmisrtpevtcvvvdvshedpevkf nwyvdgvevhnaktkpceeqygstyrcvsv Itvlhqdwlngkeykckvsnkalpapiekt iskakgqprepqvy tlppsreemtknqvsl tclvkgfypsdiavewesngqpennykttp pvldsdgsfflyskitvdksrwqqgnvfsc

- 99 043309

svmhealhnhytqkslslspgk 97. MS_l_CCxCD3 -scFc_delGK Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkclewlsyisssgstiyy adsvkgrftisrdnaknslfIqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgintwlawyqqkpgkapkll i ygasglqsgvpsrfsgsgsgtdftltissl qpedfatyycqqaksfprtfgcgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap ellggpsvfIfppkp kdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsltclvkgfypsdiavewe sngqpennykttppvldsdgs fflyskitv dksrwqqgnvf scsvmhealhnhytqksls Ispggggsggggsggggsggggsggggsgg ggsdkthtcppcpapellggpsvfIfppkp kdtlmisrtpevtcvvvdvshedpevkfnw yvdgvevhnaktkpceeqygstyrcvsvlt vlhqdwlngkeykckvsnkalpapiektis kakgqprepqvy tlppsreemtknqvsltc Ivkgfypsdiavewesngqpennykttppv Idsdgsfflyskitvdksrwqqgnvfscsv mhealhnhytqkslslspgk 98. MS_2xCD3- VH CDR1 dyymt

- 100 043309

scFc 99. MS_2xCD3scFc VH CDR2 yisssgstiyyadsvkg 100. MS_2xCD3scFc VH CDR3 drnshfdy 101. MS_2xCD3scFc VL CDR1 rasqgitrwla 102. MS_2xCD3scFc VL CDR2 aasvlqs 103. MS_2xCD3scFc VL CDR3 qqsnsfprt 104. MS_2xCD3scFc VH qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewisyisssgstiyy adsvkgrftisrdnaknslylqmnslraed tavyycardrnshfdywgqgtlvtvss 105. MS_2xCD3scFc VL diqmtqspssvsasvgdrvtitcrasqgit rwlawyqqkpgkapklliyaasvlqsgvps rfsgsgsgtdftltisslqpedfatyycqq snsfprtfgqgtkveik 106. MS_2xCD3scFc scFv qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewisyisssgstiyy adsvkgrftisrdnaknslylqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgitrwlawyqqkpgkapk lli yaasvlqsgvpsrfsgsgsgtdftltissl qpedfatyycqqsnsfprtfgqgtkveik 107. MS_2xCD3scFc Bispecific molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewisyisssgstiyy adsvkgrftisrdnaknslylqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgitrwlawyqqkpgkapk lli yaasvlqsgvpsrfsgsgsgtdftltissl qpedfatyycqqsnsfprtfgqgtkveiks

- 101 043309

ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisywayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgl1ggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkitvl 108. MS_2xCD3scFc Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewisyisssgstiyy adsvkgrftisrdnaknslylqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgitrwlawyqqkpgkapk lli yaasvlqsgvpsrfsgsgsgtdftltissl qpedfatyycqqsnsfprtfgqgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkitvlggggdkthtcppcpap ellggpsvfIfppkp kdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsItclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgnvfsc svmhealhnhytqksls Ispgkggggsggggsggggsggggsggggs ggggsdkthtcppcpapellggpsvfIfpp

- 102 043309

kpkdtlmisrtpevtcvvvdvshedpevkf nwyvdgvevhnaktkpceeqygstyrcvsv Itvlhqdwlngkeykckvsnkalpapiekt iskakgqprepqvytlppsreemtknqvsl tclvkgfypsdiavewesngqpennykttp pvldsdgsfflyskitvdksrwqq gnvfsc svmhealhnhytqkslslspgk 109. MS_2xCD3scFc_delGK Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkglewisyisssgstiyy adsvkgrftisrdnaknslylqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgitrwlawyqqkpgkapk lli yaasvlqsgvpsrfsgsgsgtdftltissl qpedfatyycqqsnsfprtfgqgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap ellggpsvfIfppkp kdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsltclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgnvfsc svmhealhnhytqksls Ispggggsggggsggggsggggsggggsgg ggsdkthtcppcpapellggpsvfIfppkp kdtlmisrtpevtcvvvdvshedpevkfnw yvdgvevhnaktkpceeqygstyrcvsvlt

- 103 043309

vlhqdwlngkeykckvsnkalpapiektis kakgqprepqvytlppsreemtknqvsltc Ivkgfypsdiavewesngqpennykttppv Idsdgsfflyskitvdksrwqqgnvfscsv mhealhnhytqkslslspgk 110. MS_2_CCxCD ³ -scFc VH qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkclewisyisssgstiyy adsvkgrftisrdnaknslylqmnslraed tavyycardrnshfdywgqgtlvtvss Ill. MS_2_CCxCD ³ -scFc VL diqmtqspssvsasvgdrvtitcrasqgit rwlawyqqkpgkapklliyaasvlqsgvps rfsgsgsgtdftltisslqpedfatyycqq snsfprtfgcgtkveik 112. MS_2_CCxCD ³ -scFc scFv qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkclewisyisssgstiyy adsvkgrftisrdnaknslylqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgitrwlawyqqkpgkapk lli yaasvlqsgvpsrfsgsgsgtdftltissl qpedfatyycqqsnsfprtfgcgtkveik 113. MS_2_CCxCD ³ -scFc Bispecific molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkclewisyisssgstiyy adsvkgrftisrdnaknslylqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgitrwlawyqqkpgkapk lli yaasvlqsgvpsrfsgsgsgtdftltissl qpedfatyycqqsnsfprtfgcgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp

- 104 043309

nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvl 114. MS_2_CCxCD3 -scFc Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkclewisyisssgstiyy adsvkgrftisrdnaknslylqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgitrwlawyqqkpgkapk lli yaasvlqsgvpsrfsgsgsgtdftltissl qpedfatyycqqsnsfprtfgcgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap ellggpsvfIfppkp kdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsitclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgnvfsc svmhealhnhytqksls Ispgkggggsggggsggggsggggsggggs ggggsdkthtcppcpapellggpsvfIfpp kpkdtlmisrtpevtcvvvdvshedpevkf nwyvdgvevhnaktkpceeqygstyrcvsv Itvlhqdwlngkeykckvsnkalpapiekt iskakgqprepqvyt lppsreemtknqvsl tclvkgfypsdiavewesngqpennykttp pvldsdgsfflyskitvdksrwqqgnvfsc

- 105 043309

svmhealhnhytqkslslspgk 115. MS_2_CCxCD3 -scFc_delGK Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dyymtwirqapgkclewisyisssgstiyy adsvkgrftisrdnaknslylqmnslraed tavyycardrnshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqgitrwlawyqqkpgkapk lli yaasvlqsgvpsrfsgsgsgtdftltissl qpedfatyycqqsnsfprtfgcgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap elIggpsvfIfppk pkdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsltclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgnvf scsvmhealhnhytqksls Ispggggsggggsggggsggggsggggsgg ggsdkthtcppcpapelIggpsvfIfppkp kdtlmisrtpevtcvvvdvshedpevkfnw yvdgvevhnaktkpceeqygstyrcvsvlt vlhqdwlngkeykckvsnkalpapiektis kakgqprepqvy tlppsreemtknqvsltc Ivkgfypsdiavewesngqpennykttppv Idsdgsfflyskitvdksrwqqgnvfscsv mhealhnhytqkslslspgk 116. MS_3xCD3- VH CDR1 dhyms

- 106 043309

scFc 117. MS_3xCD3scFc VH CDR2 yisssggiiyyadsvkg 118. MS_3xCD3scFc VH CDR3 dvgshfdy 119. MS_3xCD3scFc VL CDR1 rasqdisrwla 120. MS_3xCD3scFc VL CDR2 aasrlqs 121. MS_3xCD3scFc VL CDR3 qqaksfprt 122. MS_3xCD3scFc VH qvqlvesggglvkpggslrlscaasgftfs dhymswirqapgkglewfsyisssggiiyy adsvkgrftisrdnaknslylqmnslraed tavyуcardvgshfdywgqgtlvtvss 123. MS_3xCD3scFc VL diqmtqspssvsasvgdrvtitcrasqdis rwlawyqqkpgkapkllisaasrlqsgvps rfsgsgsgtdftltisslqpedfaiyycqq aksfprtfgqgtkveik 124. MS_3xCD3scFc scFv qvqlvesggglvkpggslrlscaasgftfs dhymswirqapgkglewfsyisssggiiyy adsvkgrftisrdnaknslylqmnslraed tavyycardvgshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqdisrwlawyqqkpgkap klli saasrlqsgvpsrfsgsgsgtdftltissl qpedfaiyycqqaksfprtfgqgtkveik 125. MS_3xCD3scFc Bispecific molecule qvqlvesggglvkpggslrlscaasgftfs dhymswirqapgkglewfsyisssggiiyy adsvkgrftisrdnaknslylqmnslraed tavyycardvgshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqdisrwlawyqqkpgkap klli saasrlqsgvpsrfsgsgsgtdftltissl qpedfaiyycqqaksfprtfgqgtkveiks

- 107 043309

ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyisywayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvl 126. MS_3xCD3scFc Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dhymswirqapgkglewfsyisssggiiyy adsvkgrftisrdnaknslylqmnslraed tavyycardvgshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqdisrwlawyqqkpgkap klli saasrlqsgvpsrfsgsgsgtdftltissl qpedfaiyycqqaksfprtfgqgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyis ywayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap ellggpsvfIfppk pkdtImisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsltclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgnvf scsvmhealhnhytqksls Ispgkggggsggggsggggsggggsggggs ggggsdkthtcppcpape11ggpsvfIfpp

- 108 043309

kpkdtlmisrtpevtcvvvdvshedpevkf nwyvdgvevhnaktkpceeqygstyrcvsv Itvlhqdwlngkeykckvsnkalpapiekt iskakgqprepqvytlppsreemtknqvsl tclvkgfypsdiavewesngqpennykttp pvldsdgsfflyskltvdksrwqq gnvfsc svmhealhnhytqkslslspgk 127. MS_3xCD3scFc_delGK Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dhymswirqapgkglewfsyisssggiiyy adsvkgrftisrdnaknslylqmnslraed tavyycardvgshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqdisrwlawyqqkpgkap klli saasrlqsgvpsrfsgsgsgtdftltissl qpedfaiyycqqaksfprtfgqgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyis ywayw gqgtlvtvssggqgsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprqliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap ellggpsvfIfpp kpkdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsltclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgnv fscsvmhealhnhytqksls Ispggggsggggsggggsggggsggggsgg ggsdkthtcppcpapellggpsvfIfppkp kdtlmisrtpevtcvvvdvshedpevkfnw yvdgvevhnaktkpceeqygstyrcvsvlt

- 109 043309

vlhqdwlngkeykckvsnkalpapiektis kakgqprepqvytlppsreemtknqvsltc Ivkgfypsdiavewesngqpennykttppv Idsdgsfflyskitvdksrwqqgnvfscsv mhealhnhytqkslslspgk 128. MS_ ³ _CCxCD ³ -scFc VH qvqlvesggglvkpggslrlscaasgftfs dhymswirqapgkclewfsyisssggiiyy adsvkgrftisrdnaknslylqmnslraed tavyycardvgshfdywgqgtlvtvss 129. MS_ ³ _CCxCD ³ -scFc VL diqmtqspssvsasvgdrvtitcrasqdis rwlawyqqkpgkapkllisaasrlqsgvps rfsgsgsgtdftltisslqpedfaiyycqq aksfprtfgcgtkveik 130. MS_ ³ _CCxCD ³ -scFc scFv qvqlvesggglvkpggslrlscaasgftfs dhymswirqapgkclewfsyisssggiiyy adsvkgrftisrdnaknslylqmnslraed tavyycardvgshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqdisrwlawyqqkpgkap klli saasrlqsgvpsrfsgsgsgtdftltissl qpedfaiyycqqaksfprtfgcgtkveik 131. MS_ ³ _CCxCD ³ -scFc bispecific molecule qvqlvesggglvkpggslrlscaasgftfs dhymswirqapgkclewfsyisssggiiyy adsvkgrftisrdnaknslylqmnslraed tavyycardvgshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqdisrwlawyqqkpgkap klli saasrlqsgvpsrfsgsgsgtdftltissl qpedfaiyycqqaksfprtfgcgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyis ywayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp

- 110 043309

nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvl 132. MS_3_CCxCD3 -scFc Bispecific HLE molecule qvqlvesggglvkpggslrlscaasgftfs dhymswirqapgkclewfsyisssggiiyy adsvkgrftisrdnaknslylqmnslraed tavyycardvgshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqdisrwlawyqqkpgkap klli saasrlqsgvpsrfsgsgsgtdftltissl qpedfaiyycqqaksfprtfgcgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgnsyis ywayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap ellggpsvfIfppk pkdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsltclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgnvf scsvmhealhnhytqksls Ispgkggggsggggsggggsggggsggggs ggggsdkthtcppcpapelIggpsvfIfpp kpkdtlmisrtpevtcvvvdvshedpevkf nwyvdgvevhnaktkpceeqygstyrcvsv Itvlhqdwlngkeykckvsnkalpapiekt iskakgqprepqvy tlppsreemtknqvsl tclvkgfypsdiavewesngqpennykttp pvldsdgsfflyskitvdksrwqqgnvfsc

- 111 043309

svmhealhnhytqkslslspgk 133. MS_ ³ _CCxCD ³ -scFc_delGK Bispecific HLE molecule qvqlvesggglvkpgqslrlscaasgftfs dhymswirqapgkclewfsyisssggiiyy adsvkgrftisrdnaknslylqmnslraed tavyycardvgshfdywgqgtlvtvssggg gsggggsggggsdiqmtqspssvsasvgdr vtitcrasqdisrwlawyqqkpgk apklli saasrlqsgvpsrfsqsgsgtdftltissl qpedfaiyycqqaksfprtfgcgtkveiks ggggsevqlvesggglvqpggslklscaas gftfnkyamnwvrqapgkglewvarirsky nnyatyyadsvkdrftisrddskntaylqm nnlktedtavyycvrhgnfgn syisywayw gqgtlvtvssggggsggggsggggsqtvvt qepsltvspggtvtltcgsstgavtsgnyp nwvqqkpgqaprgliggtkflapgtparfs gsllggkaaltlsgvqpedeaeyycvlwys nrwvfgggtkltvlggggdkthtcppcpap ellggpsvfIf ppkpkdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpc eeqygstyrcvsvltvlhqdwlngkeykck vsnkalpapiektiskakgqprepqvytlp psreemtknqvsltclvkgfypsdiavewe sngqpennykttppvldsdgsfflyskitv dksrwqqgn vfscsvmhealhnhytqksls Ispggggsggggsggggsggggsggggsgg ggsdkthtcppcpapellggpsvfIfppkp kdtlmisrtpevtcvvvdvshedpevkfnw yvdgvevhnaktkpceeqygstyrcvsvlt vlhqdwlngkeykckvsnkalpapiektis kakgqprep qvytlppsreemtknqvsltc Ivkgfypsdiavewesngqpennykttppv Idsdgsfflyskitvdksrwqqgnvfscsv mhealhnhytqkslslspgk 134. SN_1xSBE- VH CDR1 sygmh

- 112 043309

scFc 135. CH_lxCD3scFc VH CDR2 fiwydgsnkyyadsvkd 136. CH_lxCD3scFc VH CDR3 ragiigtigyyygmdv 137. CH_lxCD3scFc VL CDR1 sgdrlgekyts 138. CH_lxCD3scFc VL CDR2 qdtkrps 139. CH_lxCD3scFc VL CDR3 qawesstvv 140. CH_lxCD3scFc VH qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwydgsnkyy adsvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvss 141. CH_lxCD3scFc VL syeltqppsvsvspgqtasitcsgdrlgek ytswyqqrpgqspllviyqdtkrpsgiper fsgsnsgntatltisgtqamdeadyycqaw esstvvfgggtkltvl 142. CH_lxCD3scFc scFv qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwydgsnkyy adsvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrl gekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfggg tkltvl 143. CH_lxCD3scFc Bispecific molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwydgsnkyy adsvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrl gekytswyqqrpg

- 113 043309

qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isyway wgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 144. CH_lxCD3scFc Bispecific HLE molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwydgsnkyy adsvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrl gekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapell ggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltv dksrwqqgnvfscsvmhealhnh

- 114 043309

ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtImisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvyt lppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 145. CH_lxCD3scFc_deGK Bispecific HLE molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwydgsnkyy adsvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrl gekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkqlewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsgggqsggq gsqtvvtqepsltvspqgtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfqggtkltvlggggdktht cppc pape11ggpsvfifppkpkdtimisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff ly skltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv

- 115 043309

f1fppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvd ksrwqqg nvfscsvmhealhnhytqkslslspgk 146. SN_1_SSxSBE -scFc VH qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwydgsnkyy adsvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvss 147. CH_1_SSxESR -scFc VL syeltqppsvsvspgqtasitcsgdrlgek ytswyqqrpgqspllviyqdtkrpsgiper fsgsnsgntatltisgtqamdeadyycqaw esstvvfgcgtkltvl 148. CH_1_SSxESR -scFc scFv qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwydgsnkyy adsvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrl gekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgeg tkltvl 149. CH_l_CCxCD3 -scFc Bispecific molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwydgsnkyy adsvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrl gekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgeg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv

- 116 043309

arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 150. CH_l_CCxCD3 -scFc Bispecific HLE molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwydgsnkyy adsvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrl gekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgcg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpape llggpsvfifppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lysklt vdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp svfifppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs

- 117 043309

tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsItclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmheaIhnhytqkslslspgk 151. CH_l_CCxCD3 -scFc_delGK Bispecific HLE molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwydgsnkyy adsvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrl gekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgeg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkitvlggggdktht cppcpapell ggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsItclvkgfyps diavewesngqpennykttppvldsdgsff lyskltv dksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk

- 118 043309

ngvsltclvkgfypsdiavewesnggpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytgkslslspgk 152. CH_2xCD3scFc VH CDR1 sygmh 153. CH_2xCD3scFc VH CDR2 fiwydgsnkyyadsvkg 154. CH_2xCD3scFc VH CDR3 ragiigtigyyygmdv 155. CH_2xCD3scFc VL CDR1 sgdrlgekyts 156. CH_2xCD3scFc VL CDR2 qdtkrps 157. CH_2xCD3scFc VL CDR3 qawesstvv 158. CH_2xCD3scFc VH qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwydgsnkyy adsvkgrftisrdnskntlylgmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvss 159. CH_2xCD3scFc VL syeltqppsvsvspgqtasitcsgdrlgek ytswyqqrpgqspllviyqdtkrpsgiper fsgsnsgntatltisgtqamdeadyycqaw esstvvfgggtkltvl 160. CH_2xCD3scFc scFv qvqlvesgggvvqpggslrlscaasgftfs sуgmhwvrgapgkglewvafiwydgsnkyy adsvkgrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltgppsv svspggtasitcsgdrlge kytswygqrpg gspllviygdtkrpsgiperfsgsnsgnta tltisgtgamdeadyycgawesstvvfggg tkltvl 161. CH_2xCD3scFc Bispecify cheskaya gvglvesgggvvgpggslrlscaasgftfs sуgmhwvrgapgkglewvafiwydgsnkyy

- 119043309

molecule advertising stvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtlt cgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 162. CH_2xCD3scFc Bispecific HLE molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwydgsnkyy adsvkgrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrlge kytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycv rhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellgg psvfifppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln

- 120043309

gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdqsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp s vfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdks rwq qgnvfscsvmhealhnhytqkslslspgk 163. CH_2xCD3scFc_delGK Bispecific HLE molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwydgsnkyy adsvkgrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrlge kytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycv rhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellgg psvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps

- 121 043309

diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh utqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygs ty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsItclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 164. CH_ ² _C ^CxCD3 -scFc VH qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwydgsnkyy adsvkgrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvss 165. CH_ ² _C ^CxCD3 -scFc VL syeltqppsvsvspgqtasitcsgdrlgek ytswyqqrpgqspllviyqdtkrpsgiper fsgsnsgntatltisgtqamdeadyycqaw esstvvfgcgtkltvl 166. CH_ ² _C ^CxCD3 -scFc scFv qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwydgsnkyy adsvkgrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeItqppsv svspgqtasitcsgdrlge kytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgeg tkltvl 167. ^ch _2_ ^CCxCD3 -scFc bispecific molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwydgsnkyy adsvkgrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeItqppsv svspgqtasitcsgdrlge kytswyqqrpg

- 122 043309

qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgeg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isyway wgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 168. CH_2_SSxESR -scFc bispecific molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwydgsnkyy adsvkgrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrlge kytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgeg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycv rhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIgg psvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvd ksrwqqgnvfscsvmhealhnh

- 123 043309

ytqkslslspgkggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvyt lppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 169. CH_2_SSxESR -scFc_delGK bispecific molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwydgsnkyy adsvkgrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrlge kytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgcg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapell ggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltv dksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv

- 124 043309

fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdks rwqqg nvfscsvmhealhnhytqkslslspgk 170. CH_3xCD3scFc VH CDR1 sygmh 171. CH_3xCD3scFc VH CDR2 fiwyegsnkyyaesvkd 172. CH_3xCD3scFc VH CDR3 ragiigtigyyygmdv 173. CH_3xCD3scFc VL CDR1 sgdrlgekyts 174. CH_3xCD3scFc VL CDR2 qdtkrps 175. CH_3xCD3scFc VL CDR3 qawesstvv 176. CH_3xCD3scFc VH qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvss 177. CH_3xCD3scFc VL syeltqppsvsvspgqtasitcsgdrlgek ytswyqqrpgqspllviyqdtkrpsgiper fsgsnsgntatltisgtqamdeadyycqaw esstvvfgggtkltvl 178. CH_3xCD3scFc scFv qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdr lgekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta

- 125 043309

tltisgtqamdeadyycqawesstvvfggg tkltvl 179. CH_3xCD3scFc Bispecific molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdr lgekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntayIqmnnlktedtavy ycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 180. CH_3xCD3scFc Bispecific HLE molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdr lgekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntayIqmnnlktedtavy ycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey

- 126 043309

ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtkn qvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwy vdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsItclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 181. CH_3xCD3scFc_delGK Bispecific HLE molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkglewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdr lgekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpape llggpsvfIfppkpkdtlmisr

- 127043309

tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvm healhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytl ppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 182. CH_ ³ _SSxSBE -scFc VH qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvss 183. CH_ ³ _SSxSBE -scFc VL syeltqppsvsvspgqtasitcsgdrlgek ytswyqqrpgqspllviyqdtkrpsgiper fsgsnsgntatltisgtqamdeadyycqaw esstvvfgcgtkltvl 184. CH_ ³ _CCxCD ³ -scFc scFv qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdr lgekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgeg tkltvl 185. CH_ ³ _CCxCD ³ -scFc Bispecific qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwyegsnkyy

- 128 043309

molecule aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdrlgekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycq awesstvvfgcg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggt vtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 186. CH_ ³ _SSxESR -scFc Bispecific HLE molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdr lgekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgcg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavy ycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcp apellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln

- 129043309

gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp sv fIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksr wq qgnvfscsvmheaIhnhytqkslslspgk 187. CH_ ³ _CCxCD ³ -scFc_delGK Bispecific HLE molecule qvqlvesgggvvqpggslrlscaasgftfs sygmhwvrqapgkclewvafiwyegsnkyy aesvkdrftisrdnskntlylqmnslraed tavyycarragiigtigyyygmdvwgqgtt vtvssggggsggggsggggssyeltqppsv svspgqtasitcsgdr lgekytswyqqrpg qspllviyqdtkrpsgiperfsgsnsgnta tltisgtqamdeadyycqawesstvvfgcg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavy ycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpa pelIggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps

- 130043309

diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqy gsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 188. DL_lxCD3scFc VH CDR1 syyws 189. DL_lxCD3scFc VH CDR2 yvyysgttnynpslks 190. DL_lxCD3scFc VH CDR3 iavtgfdy 191. DL_lxCD3scFc VL CDR1 rasqrvnnnyla 192. DL_lxCD3scFc VL CDR2 gassrat 193. DL_lxCD3scFc VL CDR3 qqydrsplt 194. DL_lxCD3scFc VH qvqlqesgpglvkpsetlsltctvsggsis syywswirqppgkglewigyvyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycasiavtgfyfdywgqgtlvtvss 195. DL_lxCD3scFc VL eivltqspgtlslspgervtlscrasqrvn nnylawyqqrpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qydrspltfgggtkleik 196. DL_lxCD3scFc scFv qvqlqesgpglvkpsetlsltctvsggsis syywswirqppgkglewigyvyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycasiavtgfуfdywgqgtlvtvssgg

- 131 043309

ggsggggsggggseivltqspgtlslspge rvtlscrasqrvnnnylawyqqrpgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspltfgggtklei k 197. DL_lxCD3scFc Bispecific molecule qvqlqesgpglvkpsetlsltctvsggsis syywswirqppgkglewigyvyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycasiavtgfyfdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge rvtlscrasqrvnnnylawyqq rpgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspltfgggtklei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl qmnnlktedtavyycvrhgnfgn syisywa ywgqgtlvtvssggggsggggsggggsqtv vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvqpedeaeyycvlw ysnrwvfgggtkltvl 198. DL_lxCD3scFc Bispecific HLE molecule qvqlqesgpglvkpsetlsltctvsggsis syywswirqppgkglewigyvyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycasiavtgfyfdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge rvtlscrasqrvnnnylawyqq rpgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspltfgggtklei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl qmnnlktedtavyycvrhgnfgn syisywa ywgqgtlvtvssggggsggggsggggsqtv

- 132 043309

vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvqpedeaeyycvlw ysnrwvfgggtkitvlggggdkthtcppcp apellggpsvfIfppkpkdtlmisrtpevt cvvvdvshedpevkfnw yvdgvevhnaktk pceeqygstyrcvsvltvlhqdwlngkeyk ckvsnkalpapiektiskakgqprepqvyt IppsreemtknqvsItclvkgfypsdiave wesngqpennykttppvldsdgsfflyski tvdksrwqqgnvfscsvmhealhnhytqks Islspgkggggsggggsgggg sggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie kt1skakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewe sngqpennykt tppvidsdgsfflyskitvdksrwqqqnvf scsvmhealhnhytqkslslspgk 199. DL_lxCD3scFc_delGK Bispecific HLE molecule qvqlqesgpglvkpsetlsltctvsggsis syywswirqppgkglewigyvyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycasiavtgfyfdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge rvtlscrasqrvnnnylawyqq rpgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspiffgggtklel ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl qmnnlktedtavyycvrhgnfgnsy isywa ywgqgtlvtvssggggsggggsggggsqtv vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar

-133043309

fsgsllggkaaltlsgvqpedeaeyycvlw ysnrwvfgggtkltvlggggdkthtcppcp apellggpsvfIfppkpkdtImisrtpevt cvvvdvshedpevkfnwyvdgvevhnaktk pceeqygstyrcvsvltvlhqdwlngkeyk ckvsnkalpapiektiskakg qprepqvyt Ippsreemtknqvsltclvkgfypsdiave wesngqpennykttppvldsdgs fflyskl tvdksrwqqgnvfscsvmhealhnhytqks Islspggggsggggsggggsggggsggggs ggggsdkthtcppcpape11ggpsvfIfpp kpkdtlmisrtpevtcvvv dvshedpevkf nwyvdgvevhnaktkpceeqygstyrcvsv Itvlhqdwlngkeykckvsnkalpapiekt iskakgqprepqvytlppsreemtknqvsl tclvkgfypsdiavewesngqpennykttp pvldsdgsfflyskitvdksrwqqgnvfsc svmhealhnhytqksls lspgk 200. DL_l_CCxCD3 -scFc VH qvqlqesgpglvkpsetlsltctvsggsis syywswirqppgkclewigyvyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycasiavtgfуfdywgqgtlvtvss 201. DL_l_CCxCD3 -scFc VL eivltqspgtlslspgervtlscrasqrvn nnylawyqqrpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qydrspltfgcgtkleik 202. DL_l_CCxCD3 -scFc scFv qvqlqesgpglvkpsetlsltctvsggsis syywswirqppgkclewigyvyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycasiavtgfufdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge rvtlscrasqrvnnnylawyqq rpgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspiffgcgtklei to

- 134 043309

203. DL_l_CCxCD3 -scFc Bispecific molecule qvqlqesgpglvkpsetlsltctvsggsis syywswirqppgkclewigyvyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycasiavtgfyfdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge rvtlscrasqrvnnnylawyqq rpgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspltfgcgtklei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl qmnnlktedtavyycvrhgnf gnsyisywa ywgqgtlvtvssggggsggggsggggsqtv vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvqpedeaeyycvlw ysnrwvfgggtkltvl 204. DL_l_CCxCD3 -scFc Bispecific HLE molecule qvqlqesgpglvkpsetlsltctvsggsis syywswirqppgkclewigyvyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycasiavtgfyfdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge rvtlscrasqrvnnnylawyqq rpgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspltfgcgtklei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl qmnnlktedtavyycvrhgnf gnsyisywa ywgqgtlvtvssggggsggggsggggsqtv vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvqpedeaeyycvlw ysnrwvfgggtkltvlggggdkthtcppcp apellggps vfIfppkpkdtlmisrtpevt

-135043309

cvvvdvshedpevkfnwyvdgvevhnaktk pceeqygstyrcvsvltvlhqdwlngkeyk ckvsnkalpapiektiskakgqprepqvyt Ippsreemtkngvsltclvkgfypsdiave wesngqpennykttppvldsdgsfflyski tvdksrwgggnvfscsvmhealhnhytgks I slspgkggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytgkslslspgk 205. DL_l_CCxCD3 -scFc_delGK Bispecific HLE molecule gvglqesgpglvkpsetlsltctvsggsis syywswirgppgkclewigyvyysgttnyn pslksrvtisvdtskngfslklssvtaadt avyycasiavtgfyfdywgggtlvtvssgg ggsggggsggggseivltgspgtlslspge rvtlscrasqrvnnnylawyqqrpg qaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycggydrspiffgcgtklei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl gmnnlktedtavyycvrhgnfgnsyisywa y wgggtlvtvssggggsggggsggggsgtv vtgepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvgpedeaeyycvlw ysnrwvfgggtkltvlggggdkthtcppcp apellggpsvfIfppkpkdt lmisrtpevt cvvvdvshedpevkfnwyvdgvevhnaktk pceeqygstyrcvsvltvlhgdwlngkeyk

- 136043309

ckvsnkalpapiektiskakgqprepqvyt Ippsreemtknqvsltclvkgfypsdiave wesngqpennykttppvldsdgsfflyski tvdksrwqqgnvfscsvmhealhnhytqks Islspggggsggggsggggsggggsggggs ggggsdkthtcppcpapelIggpsvfIfpp kpkd tlmisrtpevtcvvvdvshedpevkf nwyvdgvevhnaktkpceeqygstyrcvsv Itvlhqdwlngkeykckvsnkalpapiekt iskakgqprepqvytlppsreemtknqvsl tclvkgfypsdiavewesngqpennykttp pvldsdgsfflyskitvdksrwqqgnvfsc svmhealhnhytqkslslspgk 206. DL_2xCD3scFc VH CDR1 sf yws 207. DL_2xCD3scFc VH CDR2 yiyysgttnynpslks 208. DL_2xCD3scFc VH CDR3 iavagfffdy 209. DL_2xCD3scFc VL CDR1 rasqsvnknyla 210. DL_2xCD3scFc VL CDR2 gassrat 211. DL_2xCD3scFc VL CDR3 qqydrsplt 212. DL_2xCD3scFc VH qvqlqesgpglvkpsetlsltctvsgasis sfywswirqppgkglewigyiyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycariavagfffdywgqgtlvtvss 213. DL_2xCD3scFc VL eivltqspgtlslspgeratlscrasqsvn knylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qydrspltfgggtkveik 214. DL_2xCD3scFc scFv qvqlqesgpglvkpsetlsltctvsgasis sfywswirqppgkglewigyiyysgttnyn

- 137 043309

pslksrvtisvdtsknqfslklssvtaadt avyycariavagfffdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge ratlscrasqsvnknylawyqqkpgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspiffgggt kvei k 215. DL_2xCD3scFc Bispecific molecule qvqlqesgpglvkpsetlsltctvsgasis sfywswirqppgkglewigyiyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycariavagfffdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge ratlscrasqsvnknylawyqqk pgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspiffgggtkvei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl qmnnlktedtavyycvrhgnfgnsyis ywa ywgqgtlvtvssggggsggggsggggsqtv vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvqpedeaeyycvlw ysnrwvfgggtkltvl 216. DL_2xCD3scFc Bispecific HLE molecule qvqlqesgpglvkpsetlsltctvsgasis sfywswirqppgkglewigyiyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycariavagfffdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge ratlscrasqsvnknylawyqqk pgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspiffgggtkvei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl

- 138 043309

qmnnlktedtavyycvrhgnfgnsyisywa ywgqgtlvtvssggggsggggsggggsqtv vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvqpedeaeyycvlw ysnrwvfgggtkltv lggggdkthtcppcp apellggpsvfIfppkpkdtlmisrtpevt cvvvdvshedpevkfnwyvdgvevhnaktk pceeqygstyrcvsvltvlhqdwlngkeyk ckvsnkalpapiektiskakgqprepqvyt Ippsreemtknqvsltclvkgfypsdiave wesngqpennyktt ppvldsdgsfflyski tvdksrwqqgnvfscsvmhealhnhytqks Islspgkggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqd wlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 217. DL_2xCD3scFc_delGK Bispecific HLE molecule qvqlqesgpglvkpsetlsltctvsgasis sfywswirqppgkglewigyiyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycariavagfffdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge ratiserasqsvnknylawyqqkp gqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspiffgggtkvei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl qmnnlktedtavyycvrhgnfgnsyisy wa ywgqgtlvtvssggggsggggsggggsqtv

- 139043309

vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvqpedeaeyycvlw ysnrwvfgggtkltvlggggdkthtcppcp apellggpsvfifppkpkdtlmisrtpevt cvvvdvshedpevkfnw yvdgvevhnaktk pceeqygstyrcvsvltvlhqdwlngkeyk ckvsnkalpapiektiskakgqprepqvyt Ippsreemtknqvsltclvkgfypsdiave wesngqpennykttppvldsdgsfflyski tvdksrwqqgnvfscsvmhealhnhytqks Islspggggsggggsggggs ggggsggggs ggggsdkthtcppcpapellggpsvfIfpp kpkdtlmisrtpevtcvvvdvshedpevkf nwyvdgvevhnaktkpceeqygstyrcvsv Itvlhqdwlngkeykckvsnkalpapiekt iskakgqprepqvytlppsreemtknqvsl tclvkgfypsdiavewes ngqpennykttp pvldsdgsfflyskitvdksrwqqgnvfsc svmhealhnhytqkslslspgk 218. DL_2_CCxCD ³ -scFc VH qvqlqesgpglvkpsetlsltctvsgasis sfywswirqppgkclewigyiyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycariavagfffdywgqgtlvtvss 219. DL_2_CCxCD ³ -scFc VL eivltqspgtlslspgeratlscrasqsvn knylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qydrspiffgcgtkveik 220. DL_2_CCxCD ³ -scFc scFv qvqlqesgpglvkpsetlsltctvsgasis sfywswirqppgkclewigyiyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycariavagfffdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge ratlscrasqsvnknylawyqqk pgqaprl liygassratgipdrfsgsgsgtdftltis

- 140 043309

rlepedfavyycqqydrspltfgcgtkvei k 221. DL_2_CCxCD ³ -scFc Bispecific molecule qvqlqesgpglvkpsetlsltctvsgasis sfywswirqppgkclewigyiyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycariavagfffdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge ratiserasqsvnknylawyqqkp gqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspltfgcgtkvei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl qmnnlktedtavyycvrhgnfgnsy isywa ywgqgtlvtvssggggsggggsggggsqtv vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvqpedeaeyycvlw ysnrwvfgggtkltvl 222. DL_2_CCxCD ³ -scFc Bispecific HLE molecule qvqlqesgpglvkpsetlsltctvsgasis sfywswirqppgkclewigyiyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycariavagfffdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge ratlscrasqsvnknylawyqqk pgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspiffgcgtkvei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl qmnnlktedtavyycvrhgnfgnsy isywa ywgqgtlvtvssggggsggggsggggsqtv vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvqpedeaeyycvlw

- 141 043309

ysnrwvfgggtkltvlggggdkthtcppcp apellggpsvfIfppkpkdtlmisrtpevt cvvvdvshedpevkfnwyvdgvevhnaktk pceeqygstyrcvsvltvlhqdwlngkeyk ckvsnkalpapiektiskakgqprepqvyt Ippsreemtknqvsltclv kgfypsdiave wesngqpennykttppvldsdgsfflyski tvdksrwqqgnvfscsvmhealhnhytqks Islspgkggggsggggsggggsggggsgg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpcee qygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 223. DL_2_CCxCD ³ -scFc_delGK Bispecific HLE molecule qvqlqesgpglvkpsetlsltctvsgasis sfywswirqppgkclewigyiyysgttnyn pslksrvtisvdtsknqfslklssvtaadt avyycariavagfffdywgqgtlvtvssgg ggsggggsggggseivltqspgtlslspge ratlscrasqsvnknylawyqqk pgqaprl liygassratgipdrfsgsgsgtdftltis rlepedfavyycqqydrspiffgcgtkvei ksggggsevqlvesggglvqpggslklsca asgftfnkyamnwvrqapgkglewvarirs kynnyatyyadsvkdrftisrddskntayl qmnnlktedtavyycvrhgnfgnsy isywa ywgqgtlvtvssggggsggggsggggsqtv vtqepsltvspggtvtltcgsstgavtsgn ypnwvqqkpgqaprgliggtkflapgtpar fsgsllggkaaltlsgvqpedeaeyycvlw ysnrwvfgggtkltvlggggdkthtcppcp apellggpsvf Ifppkpkdtlmisrtpevt

- 142043309

cvvvdvshedpevkfnwyvdgvevhnaktk pceeqygstyrcvsvltvlhqdwlngkeyk ckvsnkalpapiektiskakgqprepqvyt Ippsreemtknqvsltclvkgfypsdiave wesngqpennykttppvldsdgsfflyski tvdksrwqqgnvfscsvmhealhnhytq ks Islspggggsggggsggggsggggsggggs ggggsdkthtcppcpape11ggpsvfIfpp kpkdtlmisrtpevtcvvvdvshedpevkf nwyvdgvevhnaktkpceeqygstyrcvsv Itvlhqdwlngkeykckvsnkalpapiekt iskakgqprepqvytlppsreemtkn qvsl tclvkgfypsdiavewesngqpennykttp pvldsdgsfflyskitvdksrwqqgnvfsc svmhealhnhytqkslslspgk 224. DL_3xCD3scFc VH CDR1 nyymh 225. DL_3xCD3scFc VH CDR2 iinpsdgstsyaqkfqg 226. DL_3xCD3scFc VH CDR3 ggnsafysyydmdv 227. DL_3xCD3scFc VL CDR1 rssqslvyrdgntyls 228. DL_3xCD3scFc VL CDR2 kvsnwqs 229. DL_3xCD3scFc VL CDR3 mqgthwppt 230. DL_3xCD3scFc VH qvqlvqsgaevkkpgasvkvsckasgytft nyymhwvrqapglglewmgiinpsdgstsy aqkfqgrvtmtrdtstntvymdlsslrsed tavyycarggnsafysyydmdvwgqgttvt vss 231. DL_3xCD3scFc VL dvvmtqtplslpvtlgqpasiscrssqslv yrdgntylswfqqrpgqsprrliykvsnwq sgvpdrfsgggsgtdftlkisrveaedvgv

- 143 043309

yycmqgthwpptfgqgtkveik 232. DL_3xCD3scFc scFv qvqlvqsgaevkkpgasvkvsckasgytft nyymhwvrqapglglewmgiinpsdgstsy aqkfqgrvtmtrdtstntvymdlsslrsed tavyycarggnsafysyydmdvwgqgttvt vssggggsggggsggggsdvvmtqtplslp vtlgqpasiscrss qslvyrdgntylswfq qrpgqsprrliykvsnwqsgvpdrfsgggs gtdftlkisrveaedvgvyycmqgthwppt fgqgtkveik 233. DL_3xCD3scFc Bispecify cheskaya molecule qvqlvqsgaevkkpgasvkvsckasgytft nyymhwvrqapglglewmgiinpsdgstsy aqkfqgrvtmtrdtstntvymdlsslrsed tavyycarggnsafysyydmdvwgqgttvt vssggggsggggsggggsdvvmtqtplslp vtlgqpasiscrss qslvyrdgntylswfq qrpgqsprrliykvsnwqsgvpdrfsgggs gtdftlkisrveaedvgvyycmqgthwppt fgqgtkveiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddskntayl qmnnlktedtavyycvrhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvl 234. DL_3xCD3scFc Bispecific HLE molecule qvqlvqsgaevkkpgasvkvsckasgytft nyymhwvrqapglglewmgiinpsdgstsy aqkfqgrvtmtrdtstntvymdlsslrsed tavyycarggnsafysyydmdvwgqgttvt vssggggsggggsggggsdvvmtqtplslp vtlgqpasiscrss qslvyrdgntylswfq qrpgqsprrliykvsnwqsgvpdrfsgggs gtdftlkisrveaedvgvyycmqgthwppt

- 144 043309

fgqgtkveiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddskntaylqmnnlktedtavyycvrhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltc gs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkitvlggggd kthtcppcpapellggpsvfIfppkpkdt1 misrtpevtcvvvdvshedpevkfnwyvdg vevhnaktkpceeqygsty rcvsvltvlhq dwlngkeykckvsnkalpapiektiskakg qprepqvytlppsreemtknqvsltclvkg fypsdiavewesngqpennykttppvldsd gsfflyskitvdksrwqqgnvfscsvmhea Ihnhytqkslslspgkggggsggggsgggg sggggsggggsggggsdkthtc ppcpapel IggpsvfIfppkpkdtlmisrtpevtcvvv dvshedpevkfnwyvdgvevhnaktkpcee qygstyrcvsvltvlhqdwlngkeykckvs nkalpapiektiskakgqprepqvytlpps reemtknqvsItclvkgfypsdiavewesn gqpennykttppvldsdgsffly skitvdk srwqqgnvfscsvmhealhnhytqkslsls pgk 235. DL_3xCD3- Bispecific qvqlvqsgaevkkpgasvkvsckasgytft nyymhwvrqapglglewmgiinpsdgstsy aqkfqgrvtmtrdtstntvymdlsslrsed tavyycarggnsafysyydmdvwgqgttvt vssggggsggggsggggsdvvmtgtplslp scFc_delGK molecule HLE vtlgqpasiscrssqslvyrdgntylswfq qrpgqsprrliykvsnwqsgvpdrfsgggs gtdftlkisrveaedvgvyycmqgthwppt fgqgtkveiksggggsevqlvesggglvqp

- 145 043309

ggs1klscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddskntayIqmnnlktedtavyycvrhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqap rgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvlggggd kthtcppcpapellggpsvfIfppkpkdtl misrtpevtcvvvdvshedpevkfnwyvdg vevhnaktkpceeqygstyrcvsvltvlhq dwlngkeykckvsnk alpapiektiskakg qprepqvytlppsreemtknqvsltclvkg fypsdiavewesngqpennykttppvldsd gsfflyskitvdksrwqqgnvfscsvmhea Ihnhytqkslslspggggsggggsggggsg gggsggggsggggsdkthtcppcpapellg gpsvfIfppkpkdtlmisrt pevtcvvvdv shedpevkfnwyvdgvevhnaktkpceeqy gstyrcvsvltvlhqdwlngkeykckvsnk alpapiektiskakgqprepqvytlppsre emtknqvsItclvkgfypsdiavewesngq pennykttppvldsdgsfflyskitvdksr wqqgnvfscsvmhealhn hytqkslslspg to 236. DL_ ³ _CCxCD ³ -scFc VH qvqlvqsgaevkkpgasvkvsckasgytft nyymhwvrqapglclewmgiinpsdgstsy aqkfqgrvtmtrdtstntvymdlsslrsed tavyycarggnsafysyydmdvwgqgttvt vss 237. DL_ ³ _CCxCD ³ -scFc VL dvvmtqtplslpvtlgqpasiscrssqslv yrdgntylswfqqrpgqsprrliykvsnwq sgvpdrfsgggsgtdftikisrveaedvgv yycmqgthwpptfgcgtkveik 238. DL_ ³ _CCxCD ³ scFv qvqlvqsgaevkkpgasvkvsckasgytft

- 146 043309

-scFc nyymhwvrqapglclewmgiinpsdgstsy aqkfqgrvtmtrdtstntvymdlsslrsed tavyycarggnsafysyydmdvwgqgttvt vssggggsggggsggggsdvvmtqtplslp vtlgqpasiscrssqslvyrdgntylswfq qrpgqsprrliykv snwqsgvpdrfsgggs gtdftlkisrveaedvgvyycmqgthwppt fgcgtkveik 239. DL_ ³ _CCxCD ³ -scFc Bispecific molecule qvqlvqsgaevkkpgasvkvsckasgytft nyymhwvrqapglclewmgiinpsdgstsy aqkfqgrvtmtrdtstntvymdlsslrsed tavyycarggnsafysyydmdvwgqgttvt vssggggsggggsggggsdvvmtqtplslp vtlgqpasiscrss qslvyrdgntylswfq qrpgqsprrliykvsnwqsgvpdrfsgggs gtdftlkisrveaedvgvyycmqgthwppt fgcgtkveiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr ddskntayl qmnnlktedtavyycvrhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfgggtkltvl 240. DL_ ³ _CCxCD ³ -scFc Bispecific HLE molecule qvqlvqsgaevkkpgasvkvsckasgytft nyymhwvrqapglclewmgiinpsdgstsy aqkfqgrvtmtrdtstntvymdlsslrsed tavyycarggnsafysyydmdvwgqgttvt vssggggsggggsggggsdvvmtqtplslp vtlgqpasiscrss qslvyrdgntylswfq qrpgqsprrliykvsnwqsgvpdrfsgggs gtdftlkisrveaedvgvyycmqgthwppt fgcgtkveiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg

- 147 043309

lewvarirskynnyatyyadsvkdrftisr ddskntaylqmnnlktedtavyycvrhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltegs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvq ped eaeyycvlwysnrwvfgggtkltvlggggd kthtcppcpapellggpsvfIfppkpkdtl misrtpevtcvvvdvshedpevkfnwyvdg vevhnaktkpceeqygstyrcvsvltvlhq dwlngkeykckvsnkalpapiektiskakg qprepqvytlppsreemtkn qvsltclvkg fypsdiavewesngqpennykttppvldsd gsfflyskitvdksrwqqgnvfscsvmhea Ihnhytqkslslspgkggggsggggsgggg sggggsggggsggggsdkthtcppcpapel Iggpsvf1fppkpkdtlmisrtpevtcvvv dvshedpevkfnwyvdgve vhnaktkpcee qygstyrcvsvltvlhqdwlngkeykckvs nkalpapiektiskakgqprepqvytlpps reemtknqvsItclvkgfypsdiavewesn gqpennykttppvldsdgsfflyskitvdk srwqqgnvfscsvmheaIhnhytqkslsls pgk 241. DL_3_CCxCD3 -scFc_delGK Bispecific HLE molecule qvqlvqsgaevkkpgasvkvsckasgytft nyymhwvrqapglclewmgiinpsdgstsy aqkfqgrvtmtrdtstntvymdlsslrsed tavyycarggnsafysyydmdvwgqgttvt vssggggsggggsggggsdvvmtqtplsip vtlgqpasiscrssq slvyrdgntylswfq qrpgqsprrliykvsnwqsgvpdrfsgggs gtdftlkisrveaedvgvyycmqgthwppt fgcgtkveiksggggsevqlvesggglvqp ggslklscaasgftfnkyamnwvrqapgkg lewvarirskynnyatyyadsvkdrftisr

- 148 043309

ddskntaylqmnnlktedtavyycvrhgnf gnsyisywaywgqgtlvtvssggggsgggg sggggsqtvvtqepsltvspggtvtltcgs stgavtsgnypnwvqqkpgqaprgliggtk flapgtparfsgsllggkaaltlsgvqped eaeyycvlwysnrwvfggg tkltvlggggd kthtcppcpapelIggpsvfIfppkpkdt1 misrtpevtcvvvdvshedpevkfnwyvdg vevhnaktkpceeqygstyrcvsvltvlhq dwlngkeykckvsnkalpapiektiskakg qprepqvytlppsreemtknqvsltclvkg fypsdiavewesngqpenny kttppvldsd gsfflyskitvdksrwqqgnvfscsvmhea Ihnhytqkslslspggggsggggsggggsg gggsggggsggggsdkthtcppcpapel1g gpsvfIfppkpkdtlmisrtpevtcvvvdv shedpevkfnwyvdgvevhnaktkpceeqy gstyrcvsvlt vlhqdwlngkeykckvsnk alpapiektiskakgqprepqvytlppsre emtknqvsItclvkgfypsdiavewesngq pennykttppvldsdgsfflyskitvdksr wqqgnvfscsvmhealhnhytqkslslspg to 242. C19_lxCD3scFc VH CDR1 sygvs 243. C19_lxCD3scFc VH CDR2 yndpvfgsiyyaswvkg 244. C19_lxCD3scFc VH CDR3 drsyvsssgyhfnl 245. C19_lxCD3scFc VL CDR1 qasetiyssla 246. C19_lxCD3scFc VL CDR2 gasnles 247. C19_lxCD3scFc VL CDR3 qsgvysaglt

- 149 043309

248. C19_lxCD3scFc VH evqllesggglvqpggslrlscaasgftfs sygvswvrqapgkglewigyndpvfgsiyy aswvkgrftissdnskntlylqmnslraed tavyycakdrsyvsssgyhfnlwgqgtlvt vss 249. C19_lxCD3scFc VL diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkppklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgggtkveik 250. C19_lxCD3scFc scFv diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkppklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewig yndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvss 251. C19_lxCD3scFc Bispecific molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkppklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysaqltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewig yndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tay1qmnnlktedtavyy cvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvl

- 150 043309

252. C19_lxCD3scFc Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkppklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewig yndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tay1qmnnlktedtavyy cvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpape llggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 y skltvdksrwqqgnvfscsvmhealhnhy tqkslslspgkggggsggggsggggsgggg sggggsggggsdkthtcppcpapellggps vfIfppkpkdtlmisrtpevtcvvvdvshe dpevkfnwyvdgvevhnaktkpceeqygst yrcvsvltvlhqdwlngkeykckvs nkalp apiektiskakgqprepqvytlppsreemt knqvsltclvkgfypsdiavewesngqpen nykttppvldsdgsfflyskitvdksrwqq gnvfscsvmhealhnhytqkslslspgk 253. C19_l_CCxCD 3-scFc VH evqllesggglvqpggslrIscaasgftfs sygvswvrqapgkclewigyndpvfgsiyy

- 151 043309

aswvkgrftissdnskntlylqmnslraed tavyycakdrsyvsssgyhfnlwgqgtlvt vss 254. C19_l_CCxCD 3-scFc VL diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkppklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgcgtkveik 255. C19_l_CCxCD 3-scFc scFv diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkppklliygasnlesgvps rfsgsgsgtdftftisslgpediatyycgs gvysagltfgcgtkveikggggsggggsgg ggsevgllesggglvgpggslrlscaasgf tfssygvswvrgapgkclewig yndpvfgs iyyaswvkgrftissdnskntlylgmnslr aedtavyycakdrsyvsssgyhfnlwgggt Ivtvss 256. C19_l_CCxCD 3-scFc bispecific molecule digmtgspsslsasvgdrvtitcgasetiy sslawyggkpgkppklliygasnlesgvps rfsgsgsgtdftftisslgpediatyycgs gvysagltfgcgtkveikggggsggggsgg ggsevgllesggglvgpggslrlscaasgf tfssygvswvrgapgkclewigyndp vfgs iyyaswvkgrftissdnskntlylgmnslr aedtavyycakdrsyvsssgyhfnlwgggt Ivtvssggggsevglvesggglvgpggslk Iscaasgftfnkyamnwvrgapgkglewva rirskynnyatyyadsvkdrftisrddskn taylgmnnlktedtavyycvrh gnfgnsyi sywaywgggtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvggkpggaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvl 257. C19_l_CCxCD 3-scFc bispecifically cheskaya digmtgspsslsasvgdrvtitcgasetiy sslawyqqkpgkppklliygasnlesgvps

- 152 043309

molecule rfsgsgsgtdftftisslqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkclewigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyh fnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspgg tvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpapellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpce eqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspgkggggsggggsggggsgggg sggggsgg ggsdkthtcppcpapellggps vfIfppkpkdtlmisrtpevtcvvvdvshe dpevkfnwyvdgvevhnaktkpceeqygst yrcvsvltvlhqdwlngkeykckvsnkalp apiektiskakgqprepqvytlppsreemt knqvsltclvkgfypsdiavewesngqpen nyk ttppvldsdgsfflyskitvdksrwqq gnvfscsvmhealhnhytqkslslspgk 258. C19_2xCD3scFc VH CDR1 sygvs 259. C19_2xCD3scFc VH CDR2 yndpvfgsiyyaswvkg

- 153 043309

260. C19_2xCD3scFc VH CDR3 drsyvsssgyhfnl 261. C19_2xCD3scFc VL CDR1 qasetiyssla 262. C19_2xCD3scFc VL CDR2 gasnles 263. C19_2xCD3scFc VL CDR3 qsgvysaglt 264. C19_2xCD3scFc VH evqllesggglvqpggslrlscaasgftfs sygvswvrqapgkglewigyndpvfgsiyy aswvkgrftissdnskntlylqmnslraed tavyycakdrsyvsssgyhfnlwgqgtlvt vss 265. C19_2xCD3scFc VL diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftissmqpediatyycqs gvysagltfgggtkveik 266. C19_2xCD3scFc scFv diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftissmqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewig yndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvss 267. C19_2xCD3scFc Bispecific molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftissmqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewig yndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk

- 154 043309

Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tay1qmnnlktedtavyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgligg tkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvl 268. C19_2xCD3scFc Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftissmqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrIscaasgf tfssygvswvrqapgkgle wigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tay1qmnnlktedtavy ycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcp apellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspgkggggsggggsggggsgggg sggggsggggsdkthtcppcpapellggps vfIfppkpkdtlmisrtpevtcvvvdvshe

- 155 043309

dpevkfnwyvdgvevhnaktkpceeqygst yrcvsvltvlhqdwlngkeykckvsnkalp apiektiskakgqprepqvytlppsreemt knqvsItclvkgfypsdiavewesngqpen nykttppvldsdgsfflyskitvdksrwqq gnvfscsvmhealhnhytqksls lspgk 269. C19_2_CCxCD 3-scFc VH evqllesggglvqpggslrlscaasgftfs sygvswvrqapgkclewigyndpvfgsiyy aswvkgrftissdnskntlylqmnslraed tavyycakdrsyvsssgyhfnlwgqgtlvt vss 270. C19_2_CCxCD 3-scFc VL diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftissmqpediatyycqs gvysagltfgcgtkveik 271. C19_2_CCxCD 3-scFc scFv diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftissmqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvss 272. C19_2_CCxCD 3-scFc bispecifically ical molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftissmqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn

- 156 043309

taylqmnnlktedtavyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltv l 273. C19_2_CCxCD 3-scFc bispecific molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftissmqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavy ycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpa pelIggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspgkggggsggggsggggsgggg sggggsggggsdkthtcppcpapellggps vfIfppkpkdtlmisrtpevtcvvvdvshe dpevkfnwyvdgvevhnaktkpceeqygst yrcvsvltvlhqdwlngkeykckv snkalp

- 157 043309

apiektiskakgqprepqvytlppsreemt knqvsltclvkgfypsdiavewesngqpen nykttppvldsdgsfflyskitvdksrwqq gnvfscsvmhealhnhytqkslslspgk 274. C19_3xCD3scFc VH CDR1 sygvs 275. C19_3xCD3scFc VH CDR2 yndpvfgsiyyaswvkg 276. C19_3xCD3scFc VH CDR3 drsyvsssgyhfnl 277. C19_3xCD3scFc VL CDR1 qasetiyssla 278. C19_3xCD3scFc VL CDR2 gasnles 279. C19_3xCD3scFc VL CDR3 qsgvysaglt 280. C19_3xCD3scFc VH evqllesggglvqpggslrlscaasgftfs sygvswvrqapgkglewigyndpvfgsiyy aswvkgrftissdnskntlylqmnslraed tavyycakdrsyvsssgyhfnlwgqgtlvt vss 281. C19_3xCD3scFc VL diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisglqpediatyycqs gvysagltfgggtkveik 282. C19_3xCD3scFc scFv diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisglqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewig yndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvss 283. C19_3xCD3- bispecifically diqmtqspsslsasvgdrvtitcqasetiy

- 158043309

scFc cheskaya molecule sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisglqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewigyndpvfgs iyyaswvkgrftissdnskntly lqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavyycvrhgnfgnsyi sywaywgqgtlvtvss ggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvl 284. C19_3xCD3scFc bispecific molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisglqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewig yndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavyy cvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpape 11ggpsvfIfppkpkdtImisrt pevtcvvvdvshedpevkfnwyvdgvevhn

- 159043309

aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytIppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspgkggggsggggsggggsgg gg sggggsggggsdkthtcppcpapellggps vfIfppkpkdtlmisrtpevtcvvvdvshe dpevkfnwyvdgvevhnaktkpceeqygst yrcvsvltvlhqdwlngkeykckvsnkalp apiektiskakgqprepqvytlppsreemt knqvsltclvkgfypsdiavewe sngqpen nykttppvldsdgsfflyskitvdksrwqq gnvfscsvmhealhnhytqkslslspgk 285. C19_3_CCxCD 3-scFc VH evqllesggglvqpggslrlscaasgftfs sygvswvrqapgkclewigyndpvfgsiyy aswvkgrftissdnskntlylqmnslraed tavyycakdrsyvsssgyhfnlwgqgtlvt vss 286. C19_3_CCxCD 3-scFc VL diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisglqpediatyycqs gvysagltfgcgtkveik 287. C19_3_CCxCD 3-scFc scFv diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisglqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvss 288. C19_3_CCxCD 3-scFc Bispecific molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisglqpediatyycqs

- 160 043309

gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkclewigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesgg glvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkp gqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvl 289. C19_3_CCxCD 3-scFc Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisglqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwqqgt Ivtvssggggsevqlvesggglvqpgqslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedta vyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppc pape11ggpsvfIfppkpkdtImisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep

- 161 043309

qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspgkggggsggggsggggsgggg sggggsggggsdkthtcppcpapellggps vfIfppkpkdtlmisrtpevtcvvv dvshe dpevkfnwyvdgvevhnaktkpceeqygst yrcvsvltvlhqdwlngkeykckvsnkalp apiektiskakgqprepqvytlppsreemt knqvsItclvkgfypsdiavewesngqpen nykttppvldsdgsfflyskitvdksrwqq gnvfscsvmhealhnhytq kslslspgk 290. C19_4xCD3scFc VH CDR1 sygvs 291. C19_4xCD3scFc VH CDR2 yndpvfgsiyyaswvkg 292. C19_4xCD3scFc VH CDR3 drsyvsssgyhfnl 293. C19_4xCD3scFc VL CDR1 qasetiyssla 294. C19_4xCD3scFc VL CDR2 gasnles 295. C19_4xCD3scFc VL CDR3 qsgvysaglt 296. C19_4xCD3scFc VH evqllesggglvqpggslrlscaasgftfs sygvswvrqapgkglewvgyndpvfgsiyy aswvkgrftissdnskntlylqmnslraed tavyycakdrsyvsssgyhfnlwgqgtlvt vss 297. C19_4xCD3scFc VL diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgggtkveik 298. C19_4xCD3scFc scFv diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps

- 162 043309

rfsgsgsgtdftftisslqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewvgyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyh fnlwgqgt Ivtvss 299. C19_4xCD3scFc Bispecific molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglew vgyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavy ycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkitvl 300. C19_4xCD3scFc Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglew vgyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn

- 163 043309

taylgmnnlktedtavyycvrhgnfgnsyi sywaywgggtlvtvssggggsggggsgggg sgtvvtgepsltvspggtvtltcgsstgav tsgnypnwvggkpggaprgliggtkflapg tparfsgsllggkaaltlsgvgpedeaeyy cvlwysnrwvfgggtkltvlggggd kthtc ppcpapellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceegygstyrcvsvltvlhgdwlng keykckvsnkalpapiektiskakggprep gvytlppsreemtkngvsltclvkgfypsd iavewesnggpennykttppvldsd gsff1 yskltvdksrwqqgnvfscsvmhealhnhy tgkslslspgkggggsggggsggggsgggg sggggsggggsdkthtcppcpapellggps vfIfppkpkdtimisrtpevtcvvvdvshe dpevkfnwyvdgvevhnaktkpceegygst yrcvsvltvlhgdwlngkeyk ckvsnkalp apiektiskakgqprepqvytlppsreemt kngvsltclvkgfypsdiavewesnggpen nykttppvldsdgsfflyskitvdksrwqg gnvfscsvmhealhnhytgkslslspgk 301. C19_4_CCxCD 3-scFc VH evgllesggglvgpggslrlscaasgftfs sygvswvrqapgkclewvgyndpvfgsiyy aswvkgrftissdnskntlylgmnslraed tavyycakdrsyvsssgyhfnlwgggtlvt vss 302. C19_4_CCxCD 3-scFc VL diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgcgtkveik 303. C19_4_CCxCD 3-scFc scFv digmtgspsslsasvgdrvtitcgasetiy sslawyggkpgkapklliygasnlesgvps rfsgsgsgtdftftisslgpediatyycgs gvysagltfgcgtkveikggggsggggsgg

- 164 043309

ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkclewvgyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvss 304. C19_4_CCxCD 3-scFc Bispecific molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wvgyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt ivtvssggggsevqlvesggglvqpggslk iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavy ycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvl 305. C19_4_CCxCD 3-scFc Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wvgyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedta vyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg

- 165 043309

sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpapellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkf nwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspgkggg gsggggsggggsgggg sggggsggggsdkthtcppcpapellggps vfIfppkpkdtlmisrtpevtcvvvdvshe dpevkfnwyvdgvevhnaktkpceeqygst yrcvsvltvlhqdwlngkeykckvsnkalp apiektiskakgqprepqvytlppsreemt knqvsltcl vkgfypsdiavewesngqpen nykttppvldsdgsfflyskitvdksrwqq gnvfscsvmhealhnhytqkslslspgk 306. C19_lxCD3scFc_delGK Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkppklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewig yndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tay1qmnnlktedtavyy cvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg

- 166043309

tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpapellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakg qprep qvytIppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvv vdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqks lslspgk C19_l_CCxCD Bispecific diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkppklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt 307. 3- scFc_delGK molecule HLE Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tay1qmnnlktedtavyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsst gav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc

- 167043309

ppcpapellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsd gsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspggggsgqggsggggsggqgsg gggsqgggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkey kckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 308. C19_2xCD3scFc_delGK Bispecific HLE molecule diqmtqspsslsasvqdrvtitcqasetiy sslawyqqkpgkapklliygasnlesqvps rfsgsgsgtdftftissmqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrIscaasgf tfssygvswvrqapgkgle wigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpgqslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tay1qmnnlktedta vyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppc papellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn

- 168043309

aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspggggsggggsggggsgggg sg gggsggggsdkthtcppcpape11ggpsvf IfppkpkdtImisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewe sngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmheaIhnhytqkslslspgk 309. C19_2_CCxCD θ- εό Fc_delGK Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftissmqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavy ycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcp ape11ggpsvfIfppkpkdtImisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep

- 169043309

qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspggggsggggsggggsggggsg gggsggggsdkthtcppcpape11ggpsvf IfppkpkdtImisrtpevtcvvv dvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmheaIhnhytqks lslspgk 310. C19_3xCD3scFc_delGK Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisglqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglewigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwqqgt Ivtvssggggsevqlvesggglvqpgqslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpape11ggpsvfIfppkpkdtImisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsffl

- 170043309

yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckv snkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 311. C19_3_CCxCD 3- scFc_delGK Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisglqpediatyycqs gvysagltfgcgtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wigyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssgqggsevqlvesqgglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedta vyycvrhgnfgnsyi sywaywgqgtlvtvssggqgsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppc papellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsffl yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspggggsggggsggggsggggsg

- 171 043309

gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesng qpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 312. C19_4xCD3scFc_delGK Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsgtdftftisslqpediatyycqs gvysagltfgggtkveikggggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkglew vgyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tayIqmnnlktedtavy ycvrhgnfgnsy1 sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcp apellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd 1avewesngqpennykttppvldsdgsffl yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp

- 172 043309

evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspg k 313. C19_4_CCxCD 3- scFc_delGK Bispecific HLE molecule diqmtqspsslsasvgdrvtitcqasetiy sslawyqqkpgkapklliygasnlesgvps rfsgsgsqtdftftisslqpediatyycqs gvysagltfgcgtkveikqgggsggggsgg ggsevqllesggglvqpggslrlscaasgf tfssygvswvrqapgkcle wvgyndpvfgs iyyaswvkgrftissdnskntlylqmnslr aedtavyycakdrsyvsssgyhfnlwgqgt Ivtvssggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tay1qmnnlktedta vyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppc papellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsffl yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvs nkalpap

- 173 043309

iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 314. FL_lxCD3scFc VH CDR1 narmgvs 315. FL_lxCD3scFc VH CDR2 nifsndeksystslks 316. FL_lxCD3scFc VH CDR3 ivgygsgwygyfdy 317. FL_lxCD3scFc VL CDR1 rasqgirndlg 318. FL_lxCD3scFc VL CDR2 aasslqs 319. FL_lxCD3scFc VL CDR3 Iqhnsyplt 320. FL_lxCD3scFc VH qvtlkesgpalvkptetltltctvsgfsis narmgvswirqppgkalewlanifsndeks ystslksrltiskgtsksqvvltmtnmdpe dtatyycarivgygsgwygyfdywgqgtlv tvss 321. FL_lxCD3scFc VL diqmtqspsslsasvgdrvtitcrasqgir ndlgwyqqkpgkapqrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgggtkveiks 322. FL_lxCD3scFc scFv qvtlkesgpalvkptetltltctvsgfsis narmgvswirqppgkalewlanifsndeks ystslksrltiskgtsksqvvltmtnmdpe dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlgw yqqkpg kapqrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveik 323. FL_lxCD3- Bispecify qvtlkesgpalvkptetltltctvsgfsis

- 174043309

scFc cheskaya molecule narmgvswirqppgkalewlanifsndeks ystslksrltiskgtsksqvvltmtnmdpe dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlgwyqqkpg kapqrliyaasslqsgvpsr fsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggs ggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 324. FL_lxCD3scFc Bispecific HLE molecule qvtlkesgpalvkptetltltctvsgfsis narmgvswirqppgkalewlanifsndeks ystslksrltiskgtsksqvvltmtnmdpe dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlgw yqqkpg kapqrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgn sy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfpp kpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh

-175043309

naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsItclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsItclvkgfypsdiavewe sngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmheaIhnhytqkslslspgk 325. FL_l_CCxCD3 -scFc VH qvtlkesgpalvkptetltltctvsgfsis narmgvswirqppgkclewlanifsndeks ystslksrltiskgtsksqvvltmtnmdpe dtatyycarivgygsgwygyfdywgqgtlv tvss 326. FL_l_CCxCD3 -scFc VL diqmtqspsslsasvgdrvtitcrasqgir ndlgwyqqkpgkapqrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgcgtkveik 327. FL_l_CCxCD3 -scFc scFv qvtlkesgpalvkptetltltctvsgfsis narmgvswirqppgkclewlanifsndeks ystslksrltiskgtsksqvvltmtnmdpe dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlgw yqqkpg kapqrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiks 328. FL_l_CCxCD ³ -scFc Bispecific molecule qvtlkesgpalvkptetltltctvsgfsis narmgvswirqppgkclewlanifsndeks ystslksrltiskgtsksqvvltmtnmdpe

- 176 043309

dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssi sasvgdrvtitcrasqgirndlgwyqqkpg kapqrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpgg sl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgligg tkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 329. FL_l_CCxCD3 -scFc Bispecific HLE molecule qvtlkesgpalvkptetltltctvsgfsis narmgvswirqppgkclewlanifsndeks ystslksrltiskgtsksqvvltmtnmdpe dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssi sasvgdrvtitcrasqgirndlgwy qqkpg kapqrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIggpsvfIfppk pkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre

- 177043309

pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvv vdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytq kslslspgk 330. FL_2xCD3scFc VH CDR1 narmgvs 331. FL_2xCD3scFc VH CDR2 hifsndeksystslkn 332. FL_2xCD3scFc VH CDR3 ivgygsgwygffdy 333. FL_2xCD3scFc VL CDR1 rasqgirndlg 334. FL_2xCD3scFc VL CDR2 aastlqs 335. FL_2xCD3scFc VL CDR3 Iqhnsyplt 336. FL_2xCD3scFc VH qvtlkesgptlvkptetltltctlsgfsin narmgvswirqppgkalewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygsgwygffdywgqgtlv tvss 337. FL_2xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqgir ndlgwyqqkpgkapkrliyaastlqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgggtkveik 338. FL_2xCD3scFc scFv qvtlkesgptlvkptetltltctlsgfsin narmgvswirqppgkalewlahifsndeks

- 178 043309

ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygsgwygffdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfaty yclqhnsypltfggg tkveiks 339. FL_2xCD3scFc Bispecific molecule qvtlkesgptlvkptetltltctlsgfsin narmgvswirqppgkalewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygsgwygffdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndl gwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkitvl 340. FL_2xCD3scFc Bispecific HLE molecule qvtlkesgptlvkptetltltctlsgfsin narmgvswirqppgkalewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygsgwygffdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndl gwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk

- 179 043309

ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltv lggggdktht cppcpapellggpsvf1fppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennyk ttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfifppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcv svltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 341. FL_2_CCxCD ³ -scFc VH qvtlkesgptlvkptetltltctlsgfsin narmgvswirqppgkclewlahi fsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygsgwygffdywgqgtlv tvss 342. FL_2_CCxCD ³ -scFc VL diqmtqspsslsasvgdrvtitcrasqgir ndlgwyqqkpgkapkrliyaastlqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgcgtkveik 343. FL_2_CCxCD ³ -scFc scFv qvtlkesgptlvkptetltltctlsgfsin narmgvswirqppgkclewlahi fsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygsgwygffdywgqgtlv

- 180 043309

tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiks 344. FL_ ² _CCxCD ³ -scFc Bispecific molecule qvtlkesgptlvkptetltltctlsgfsin narmgvswirqppgkclewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygsgwygffdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndl gwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 345. FL_ ² _CCxCD ³ -scFc Bispecific HLE molecule qvtlkesgptlvkptetltltctlsgfsin narmgvswirqppgkclewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygsgwygffdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndl gwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsggg

- 181 043309

gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpev kfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkg gggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvs ltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmheaIhnhytqkslslspgk 346. FL_3xCD3scFc VH CDR1 narmavs 347. FL_3xCD3scFc VH CDR2 hifsndeksystslks 348. FL_3xCD3scFc VH CDR3 ivgygsgwygyfdy 349. FL_3xCD3scFc VL CDR1 rasqdirndlg 350. FL_3xCD3scFc VL CDR2 aastlqs 351. FL_3xCD3scFc VL CDR3 Iqhnsyplt 352. FL_3xCD3scFc VH qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgktlewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv

- 182 043309

dtatyycarivgygsgwygyfdywgqgtlv tvss 353. FL_3xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqdir ndlgwyqqkpgkapkrliyaastlqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgggtkveik 354. FL_3xCD3scFc scFv qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgktlewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirndlg wyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiks 355. FL_3xCD3scFc Bispecific molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgktlewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirndlg wyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgn fgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 356. FL_3xCD3scFc Bispecific molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgktlewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv

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HLE dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdigmtgspssl sasvgdrvtitcrasqdirndlgwyggkpg kapkrliyaastlgsgvpsrfsgsgsgtef tltisslgpedfatyyclghnsypltfggg tkveiksggggsevglvesggglvgpggs l klscaasgftfnkyamnwvrgapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylgmnnlktedtavyycvrhgnfgnsy isywaywgggtlvtvssggggsggggsggg gsgtvvtgepsltvspggtvtltcgsstga vtsgnypnwvggkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvgpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtImisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceegygstyrcvsvltvlhgdwln gkeykckvsnkalpapiektis kakggpre pgvytlppsreemtkngvsltclvkgfyps diavewesnggpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytgkslslspgkggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtImisrtpevtc vvvdvsh edpevkfnwyvdgvevhnaktkpceegygs tyrcvsvltvlhgdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tkngvsltclvkgfypsdiavewesnggpe nnykttppvldsdgsfflyskitvdksrwg qgnvfscsvmhealhnhytg kslslspgk 357. FL_3_CCxCD3 -scFc VH gvtlkesgpalvkptetltltctlsgfsin narmavswirgppgkclewlahifsndeks ystslksrltiskdtskggvvltmtnmdpv dtatyycarivgygsgwygyfdywgggtlv tvss

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358. FL_ ³ _CCxCD ³ -scFc VL diqmtqspsslsasvgdrvtitcrasqdir ndlgwyqqkpgkapkrliyaastlqsgvps rfsgsqsgteftltisslqpedfatyyclq hnsypltfgcgtkveik 359. FL_ ³ _CCxCD ³ -scFc scFv qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgkclewlahi fsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssgqggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirnd lgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiks 360. FL_ ³ _CCxCD ³ -scFc Bispecific molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgkclewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirndlg wyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgn fgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlg 361. FL_ ³ _CCxCD ³ -scFc Bispecific HLE molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgkclewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl

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sasvgdrvtitcrasqdirndlgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrd dsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltv lggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykt tppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvs vltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmheaIhnhytqkslslspgk 362. FL_4xCD3scFc VH CDR1 nakmgvs 363. FL_4xCD3scFc VH CDR2 hifsndeksystslks 364. FL_4xCD3scFc VH CDR3 ivgygsgwygyfdy 365. FL_4xCD3- VL CDR1 rasqdirddlg

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scFc 366. FL_4xCD3scFc VL CDR2 gastlqs 367. FL_4xCD3scFc VL CDR3 Iqhnsyplt 368. FL_4xCD3scFc VH qvtlkesgpalvkptetltltctlsgfsin nakmgvswirqppgkalewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvss 369. FL_4xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqdir ddlgwyqqkpgnapkrliygastlqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgggtkvdik 370. FL_4xCD3scFc scFv qvtlkesgpalvkptetltltctlsgfsin nakmgvswirqppgkalewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirddl gwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkvdiks 371. FL_4xCD3scFc Bispecific molecule qvtlkesgpalvkptetltltctlsgfsin nakmgvswirqppgkalewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirddl gwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy

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isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 372. FL_4xCD3scFc Bispecific HLE molecule qvtlkesgpalvkptetltltctlsgfsin nakmgvswirqppgkalewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirddl gwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsv fIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksr wqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnk al papiektiskakgqprepqvytlppsreem

- 188 043309

tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 373. FL_4_CCxCD3 -scFc VH qvtlkesgpalvkptetltltctlsgfsin nakmgvswirqppgkclewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvss 374. FL_4_CCxCD3 -scFc VL diqmtqspsslsasvgdrvtitcrasqdir ddlgwyqqkpgnapkrliygastlqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgcgtkvdik 375. FL_4_CCxCD3 -scFc scFv qvtlkesgpalvkptetltltctlsgfsin nakmgvswirqppgkclewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirddl gwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgcg tkvdiks 376. FL_4_CCxCD3 -scFc Bispecific molecule qvtlkesgpalvkptetltltctlsgfsin nakmgvswirqppgkclewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirddl gwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgcg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga

- 189 043309

vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 377. FL_4_CCxCD3 -scFc Bispecific HLE molecule qvtlkesgpalvkptetltltctlsgfsin nakmgvswirqppgkclewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirddl gwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht eppepapelggpsvf Ifppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrw qqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthteppepapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papie ktiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq

- 190 043309

qgnvfscsvmhealhnhytqkslslspgk 378. FL_5xCD3scFc VH CDR1 narmavs 379. FL_5xCD3scFc VH CDR2 hitsndeksystslks 380. FL_5xCD3scFc VH CDR3 ivgygsgwygyfdy 381. FL_5xCD3scFc VL CDR1 rasqdirydla 382. FL_5xCD3scFc VL CDR2 aasslqs 383. FL_5xCD3scFc VL CDR3 Iqhnfyplt 384. FL_5xCD3scFc VH qvtlkesgpvlvkptetltltctvsgfsir narmavswirqppgktlewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvss 385. FL_5xCD3scFc VL diqmtqspssvsasvgdrvtitcrasqdir ydlawyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnfypltfgggtkveik 386. FL_5xCD3scFc scFv qvtlkesgpvlvkptetltltctvsgfsir narmavswirqppgktlewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssv sasvgdrvtitcrasqdiryd lawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnfypltfggg tkveiks 387. FL_5xCD3scFc Bispecific molecule qvtlkesgpvlvkptetltltctvsgfsir narmavswirqppgktlewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv

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tvssggggsggggsggggsdiqmtqspssv sasvgdrvtitcrasqdirydlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnfypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgk glewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqped eaey ycvlwysnrwvfgggtkitvl 388. FL_5xCD3scFc Bispecific HLE molecule qvtlkesgpvlvkptetltltctvsgfsir narmavswirqppgktlewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssv sasvqdrvtitcrasqdiryd lawyqqkpg kapkrliyaasslqsqvpsrfsgsgsqtef tltisslqpedfatyyclqhnfypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgn fgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkitvlggggdktht cppcpapellggpsvf Ifppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsItclvkgfyps

- 192043309

diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktk pceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 389. FL_5_CCxCD ³ -scFc VH qvtlkesgpvlvkptetltltctvsgfsir narmavswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvss 390. FL_5_CCxCD ³ -scFc VL diqmtqspssvsasvgdrvtitcrasqdir ydlawyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnfypltfgcgtkveik 391. FL_5_CCxCD ³ -scFc scFv qvtlkesgpvlvkptetltltctvsgfsir narmavswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssv sasvgdrvtitcrasqdiryd lawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnfypltfgeg tkveiks 392. FL_5_CCxCD ³ -scFc Bispecific molecule qvtlkesgpvlvkptetltltctvsgfsir narmavswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssv sasvgdrvtitcrasqdiryd lawyqqkpg

- 193 043309

kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnfypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isyway wgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl FL_5_CCxCD ³ Bispecific qvtlkesgpvlvkptetltltctvsgfsir narmavswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssv sasvgdrvtitcrasqdiryd lawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnfypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgn fgnsy 393. -scFc molecule HLE isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfpp kpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqq gnvfscsvmhealhnh

- 194 043309

ytqkslslspgkggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtImisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvyt lppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmheaIhnhytqkslslspgk 394. FL_6xCD3scFc VH CDR1 narmgvs 395. FL_6xCD3scFc VH CDR2 hifsndeksfstslkn 396. FL_6xCD3scFc VH CDR3 mvgygsgwyayfdy 397. FL_6xCD3scFc VL CDR1 rasqsissyln 398. FL_6xCD3scFc VL CDR2 aasslqs 399. FL_6xCD3scFc VL CDR3 Iqhnsyplt 400. FL_6xCD3scFc VH qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks fstslknrltis kdt s ks qvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtqv tvss 401. FL_6xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqsis sylnwyqqkpgkapklliyaasslqsgvps rfsgsgsgtdftltisslqpedfatyyclq hnsypltfgggtkveik 402. FL_6xCD3scFc scFv qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks fstslknrltis kdt s ks qvvltmtnmdpv

- 195 043309

dtatyycarmvgygsgwyayfdywgqgtqv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqsissylnwyqqkpg kapklliyaasslqsgvpsrfsgsgsgtdf tltisslqpedfatyyclqhnsypltfggg tkveiks 403. FL_6xCD3scFc Bispecific molecule qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks fstslknrltis kdt s ks qvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtqv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcra sqsissylnwyqqkpg kapklliyaasslqsgvpsrfsgsgsgtdf tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 404. FL_6xCD3scFc Bispecific HLE molecule qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks fstslknrltis kdt s ks qvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtqv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcra sqsissylnwyqqkpg kapklliyaasslqsgvpsrfsgsgsgtdf tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyy cvrhgnfgnsy

- 196 043309

isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvf1f ppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennyкttppvldsdgsff lyskltvdksrwq qgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal pa piektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 405. FL_6_CCxCD ³ -scFc VH qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkclewlahi fsndeks fstslknrltis kdt s to s qvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtqv tvss 406. FL_6_CCxCD ³ -scFc VL diqmtqspsslsasvgdrvtitcrasqsis sylnwyqqkpgkapklliyaasslqsgvps rfsgsgsgtdftltisslqpedfatyyclq hnsypltfgcgtkveik 407. FL_6_CCxCD ³ -scFc scFv qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks fstslknrltis kdt s to s qvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtqv tvssggggsggggsggggsdiqmtqspssl

- 197 043309

sasvgdrvtitcrasqsissylnwyqqkpg kapklliyaasslgsgvpsrfsgsgsgtdf tltisslgpedfatyyclghnsypltfgeg tkveiks 408. FL_6_CCxCD ³ -scFc Bispecific molecule gvtlkesgpvlvkptgtltltctfsgfsis narmgvswirgppgkclewlahifsndeks fstslknrltis kdt s ks gvvltmtnmdpv dtatyycarmvgygsgwyayfdywgggtgv tvssggggsggggsggggsdigmtgspssl sasvgdrvtitcrasgsiss ylnwyggkpg kapklliyaasslgsgvpsrfsgsgsgtdf tltisslgpedfatyyclghnsypltfgeg tkveiksggggsevglvesggglvgpggsl klscaasgftfnkyamnwvrgapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylgmnnlktedtavyycvrhgnf gnsy isywaywgggtlvtvssggggsggggsggg gsgtvvtgepsltvspggtvtltcgsstga vtsgnypnwvggkpggaprgliggtkflap gtparfsgsllggkaaltlsgvgpedeaey ycvlwysnrwvfgggtkitvl 409. FL_6_CCxCD ³ -scFc Bispecific HLE molecule gvtlkesgpvlvkptgtltltctfsgfsis narmgvswirgppgkclewlahifsndeks fstslknrltis kdt s ks qvvltmtnmdpv dtatyycarmvgygsgwyayfdywgggtgv tvssggggsggggsggggsdigmtgspssl sasvgdrvtitcrasqsis sylnwyqqkpg kapklliyaasslgsgvpsrfsgsgsgtdf tltisslgpedfatyyclghnsypltfgeg tkveiksggggsevglvesggglvgpggsl klscaasgftfnkyamnwvrgapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylgmnnlktedtavyycvrh gnfgnsy isywaywgggtlvtvssggggsggggsggg gsgtvvtgepsltvspggtvtltcgsstga

- 198 043309

vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygsty rcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdktht cppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvld sdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 410. FL_7xCD3scFc VH CDR1 narmgvs 411. FL_7xCD3scFc VH CDR2 hifsndeksystslkn 412. FL_7xCD3scFc VH CDR3 ivgygtgwfgyfdy 413. FL_7xCD3scFc VL CDR1 rasqdirtdla 414. FL_7xCD3scFc VL CDR2 aasslqs 415. FL_7xCD3scFc VL CDR3 Iqhnryplt 416. FL_7xCD3scFc VH qvtlkesgptlvkptetltltctvsgfsin narmgvswirqppgkalewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygtgwfgyfdywgqgtqv

- 199 043309

tvss 417. FL_7xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqdir tdlawyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnrypltfgggtkvdik 418. FL_7xCD3scFc scFv qvtlkesgptlvkptetltltctvsgfsin narmgvswirqppgkalewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygtgwfgyfdywgqgtqv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdi rtdlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnrypltfggg tkvdiks 419. FL_7xCD3scFc Bispecific molecule qvtlkesgptlvkptetltltctvsgfsin narmgvswirqppgkalewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygtgwfgyfdywgqgtqv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdi rtdlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnrypltfggg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntay1qmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 420. FL_7xCD3scFc Bispecific HLE molecule qvtlkesgptlvkptetltltctvsgfsin narmgvswirqppgkalewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygtgwfgyfdywgqgtqv

- 200 043309

tvssggggsggggsggggsdiqmtqspssi sasvgdrvtitcrasqdirtdlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnrypltfggg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglew v arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknq vsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvd gvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsItclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 421. FL_7_CCxCD3 -scFc VH qvtlkesgptlvkptetltltctvsgfsin narmgvswirqppgkclewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygtgwfgyfdywgqgtqv tvss 422. FL_7_CCxCD3 VL diqmtqspsslsasvgdrvtitcrasqdir

- 201 043309

-scFc tdlawyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnrypltfgcgtkvdik 423. FL_7_CCxCD3 -scFc scFv qvtlkesgptlvkptetltltctvsgfsin narmgvswirqppgkclewlahi fsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygtgwfgyfdywgqgtqv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasq dirtdlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnrypltfgeg tkvdiks 424. FL_7_CCxCD ³ -scFc Bispecific molecule qvtlkesgptlvkptetltltctvsgfsin narmgvswirqppgkclewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygtgwfgyfdywgqgtqv tvssgqggsggggsggggsdiqmtqspssl sasvgdrvtitcrasq dirtdlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnrypltfgeg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 425. FL_7_CCxCD ³ -scFc Bispecific HLE molecule qvtlkesgptlvkptetltltctvsgfsin narmgvswirqppgkclewlahi fsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygtgwfgyfdywgqgtqv tvssgqggsggggsggggsdiqmtqspssl sasvgdrvtitcras qdirtdlawyqqkpg

- 202 043309

kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnrypltfgcg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isyway wgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkd tlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfsc svmhealhnh ytqkslslspgkggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakg qprepqvytlppsreem tknqvsItclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 426. FL_8xCD3scFc VH CDR1 narmavs 427. FL_8xCD3scFc VH CDR2 hifsndeksystslks 428. FL_8xCD3scFc VH CDR3 ivgygtgwygffdy 429. FL_8xCD3scFc VL CDR1 rasqgirndla

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430. FL_8xCD3scFc VL CDR2 aasslqs 431. FL_8xCD3scFc VL CDR3 Iqhnsyplt 432. FL_8xCD3- SCFc VH qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgktlewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpe dtatyycarivgygtgwygffdywgqgilv tvss 433. FL_8xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqgir ndlawyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgggtkveik 434. FL_8xCD3scFc scFv qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgktlewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlawyq qkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiks 435. FL_8xCD3scFc Bispecific molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgktlewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlawyq qkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy is ywaywgqgtlvtvssggggsggggsggg

-204043309

gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkitvl 436. FL_8xCD3scFc Bispecific HLE molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgktlewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlawyq qkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy is ywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkitvlggggdktht cppcpapellggpsvfIfppkp kdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsItclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnv fscsvmhealhnh ytqkslslspgkgggqsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiek tiskakgqprepqvytlppsreem tknqvsItclvkgfypsdiavewesngqpe

- 205 043309

nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 437. FL_8_CCxCD ³ -scFc VH qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpe dtatyycarivgygtgwygffdywgqgilv tvss 438. FL_8_CCxCD ³ -scFc VL diqmtqspsslsasvgdrvtitcrasqgir ndlawyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgcgtkveik 439. FL_8_CCxCD ³ -scFc scFv qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlawyq qkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiks 440. FL_8_CCxCD ³ -scFc Bispecific molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlawyq qkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy is ywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap

- 206 043309

gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 441. FL_8_CCxCD ³ -scFc Bispecific HLE molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlawyq qkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy is ywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkp kdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnv fscsvmhealhnh ytqkslslspgkggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektis kakgqprepqvytlppsreem tknqvs1tclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk

- 207 043309

442. FL_9xCD3scFc VH CDR1 yarmgvs 443. FL_9xCD3scFc VH CDR2 hifsndeksystslks 444. FL_9xCD3scFc VH CDR3 mpeyssgwsgafdi 445. FL_9xCD3scFc VL CDR1 rasqdirndla 446. FL_9xCD3scFc VL CDR2 aasslqs 447. FL_9xCD3scFc VL CDR3 Iqhnsyplt 448. FL_9xCD3scFc VH qvtlkesgptlvkptetltltctfsgfsir yarmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvss 449. FL_9xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqdir ndlawyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgggtkleik 450. FL_9xCD3scFc scFv qvtlkesgptlvkptetltltctfsgfsir yarmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqd irndlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkleiks 451. FL_9xCD3scFc Bispecific molecule qvtlkesgptlvkptetltltctfsgfsir yarmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl

- 208 043309

sasvgdrvtitcrasqdirndlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkleiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntay1qmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 452. FL_9xCD3scFc Bispecific HLE molecule qvtlkesgptlvkptetltltctfsgfsir yarmqvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqd irndlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkleiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntay1qmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggps vfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff

-209043309

lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtImisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqd wlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 453. FL_9_CCxCD3 -scFc VH qvtlkesgptlvkptetltltctfsgfsir yarmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvss 454. FL_9_CCxCD3 -scFc VL diqmtqspsslsasvgdrvtitcrasqdir ndlawyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgcgtkleik 455. FL_9_CCxCD3 -scFc scFv qvtlkesgptlvkptetltltctfsgfsir yarmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqd irndlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkleiks 456. FL_9_CCxCD3 -scFc Bispecific molecule Qvtlkesgptlvkptetltltctfsgfsir yarmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdir ndlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef

- 210 043309

tltisslqpedfatyyclqhnsypltfgcg tkleiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsq tvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 457. FL_9_CCxCD3 -scFc Bispecific HLE molecule qvtlkesgptlvkptetltltctfsgfsir yarmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqd irndlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgcg tkleiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIggps vfifppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdks rwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg

- 211 043309

gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceegygs tyrcvsvltvlhgdwlngkeykckvsnkal papiektiskakggprepgvytlppsreem tkngvsltclvkgfypsdiavewes nggpe nnykttppvldsdgsfflyskitvdksrwg qgnvfscsvmhealhnhytqkslslspgk 458. FL_10xCD3scFc VH CDR1 narmgvs 459. FL_10xCD3scFc VH CDR2 hifsndeksystslks 460. FL_10xCD3scFc VH CDR3 mpeyssgwsgafdi 461. FL_10xCD3scFc VL CDR1 rasqdirddlg 462. FL_10xCD3scFc VL CDR2 gastlqs 463. FL_10xCD3scFc VL CDR3 Iqhnsyplt 464. FL_10xCD3scFc VH qvtlkesgpvlvkptetltltctvsgfsfr narmgvswirgppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvss 465. FL_10xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqdir ddlgwyqqkpgnapkrliygastlqsgvps rfsgsgsgteftltisslgpedfatyyclg hnsypltfgggtkvdik 466. FL_10xCD3scFc scFv qvtlkesgpvlvkptetltltctvsgfsfr narmgvswirgppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv

- 212 043309

tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirddlgwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkvdiks 467. FL_10xCD3scFc Bispecific molecule qvtlkesgpvlvkptetltltctvsgfsfr narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdi rddlgwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntay1qmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 468. FL_10xCD3scFc Bispecific HLE molecule qvtlkesgpvlvkptetltltctvsgfsfr narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdi rddlgwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg

- 213 043309

gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvf1fppkpkdtlmisr tpevtcvvvdvshedp evkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspg kggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfifppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqv sltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 469. FL_10_CCxCD 3-scFc VH qvtlkesgpvlvkptetltltctvsgfsfr narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvss 470. FL_10_CCxCD 3-scFc VL diqmtqspsslsasvgdrvtitcrasqdir ddlgwyqqkpgnapkrliygastlqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgcgtkvdik 471. FL_10_CCxCD 3-scFc scFv qvtlkesgpvlvkptetltltctvsgfsfr narmgvswirqppgkclewlahi fsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasq dirddlgwyqqkpg

- 214 043309

napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkvdiks 472. FL_10_CCxCD 3-scFc Bispecific molecule qvtlkesgpvlvkptetltltctvsgfsfr narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdi rddlgwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkitvl 473. FL_10_CCxCD 3-scFc Bispecific HLE molecule qvtlkesgpvlvkptetltltctvsgfsfr narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdi rddlgwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap

- 215 043309

gtparfsgsllggkaaltlsgvqpedeaey уcvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiek tiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpev tcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmheal hnhytqkslslspgk 474. FL_llxCD3scFc VH CDR1 narmgvs 475. FL_llxCD3scFc VH CDR2 hifsndeksystslks 476. FL_llxCD3scFc VH CDR3 mpeyssgwsgafdi 477. FL_llxCD3scFc VL CDR1 rasqdigydlg 478. FL_llxCD3scFc VL CDR2 aastlqs 479. FL_llxCD3scFc VL CDR3 Iqhnsfpwt 480. FL_llxCD3scFc VH qvtlkesgpalvkptetltltctvsgfsfr narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvss

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481. FL_llxCD3scFc VL diqmtqspsslsasvgdrvtitcrasqdig ydlgwyqqkpgkapkrliyaastlqsgvps rfsgsgsgteftliisslqpedfatyyclq hnsfpwtfgqgtkveik 482. FL_llxCD3scFc scFv qvtlkesgpalvkptetltltctvsgfsfr narmgvswirqppgkalewlahi fsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdi gydlgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tliisslqpedfatyyclqhnsfpwtfgqg tkveiks 483. FL_llxCD3scFc Bispecific molecule qvtlkesgpalvkptetltltctvsgfsfr narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdigy dlgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tliisslqpedfatyyclqhnsfpwtfgqg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavy ycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 484. FL_llxCD3scFc Bispecific HLE molecule qvtlkesgpalvkptetltltctvsgfsfr narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl

- 217 043309

sasvgdrvtitcrasqdigydlgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tliisslqpedfatyyclqhnsfpwtfgqg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdr ftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfggg tkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngq pennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthteppepapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrc vsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 485. FL_ll_CCxCD 3-scFc VH qvtlkesgpalvkptetltltctvsgfsfr narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvss 486. FL_ll_CCxCD 3-scFc VL diqmtqspsslsasvgdrvtitcrasqdig ydlgwyqqkpgkapkrliyaastlqsgvps

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rfsgsgsgteftliisslqpedfatyyclq hnsfpwtfgcgtkveik 487. FL_ll_CCxCD 3-scFc scFv qvtlkesgpalvkptetltltctvsgfsfr narmgvswirqppgkclewlahi fsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdi gydlgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tliisslqpedfatyyclqhnsfpwtfgcg tkveiks 488. FL_ll_CCxCD 3-scFc Bispecific molecule qvtlkesgpalvkptetltltctvsgfsfr narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdigy dlgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tliisslqpedfatyyclqhnsfpwtfgcg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavy ycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 489. FL_ll_CCxCD 3-scFc Bispecific HLE molecule qvtlkesgpalvkptetltltctvsgfsfr narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdigy dlgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef

- 219 043309

tliisslqpedfatyyclqhnsfpwtfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gs qtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfn wyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsgg ggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvs1tcl vkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 490. FL_12xCD3scFc VH CDR1 narmgvs 491. FL_12xCD3scFc VH CDR2 hifsndeksyrtslks 492. FL_12xCD3scFc VH CDR3 ivgygsgwyayfdy 493. FL_12xCD3scFc VL CDR1 rasqgirndlg 494. FL_12xCD3- VL CDR2 aasslqs

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scFc 495. FL_12xCD3scFc VL CDR3 Iqhnsyplt 496. FL_12xCD3scFc VH qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks yrtslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwyayfdywgqgtlv tvss 497. FL_12xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqgir ndlgwyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgggtkveik 498. FL_12xCD3scFc scFv qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks yrtslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsqwyayfdywgqqtlv tvssqgggsggggsgqggsdiqmtqspssl sasvgdrvtitcrasqgir ndlgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiks 499. FL_12xCD3scFc Bispecific molecule qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks yrtslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirnd lgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntay1qmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga

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vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 500. FL_12xCD3scFc Bispecific HLE molecule qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks yrtslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirnd lgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpape11ggps vfIfppkpkdtImisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdks rwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtImisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsn kal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq

- 222 043309

qgnvfscsvmhealhnhytqkslslspgk 501. FL_12_CCxCD 3-scFc VH qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks yrtslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwyayfdywgqgtlv tvss 502. FL_12_CCxCD 3-scFc VL diqmtqspsslsasvgdrvtitcrasqgir ndlgwyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgcgtkveik 503. FL_12_CCxCD 3-scFc scFv qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks yrtslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirnd lgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiks 504. FL_12_CCxCD 3-scFc Bispecific molecule qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks yrtslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirnd lgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey

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уcvlwysnrwvfgggtkltvl 505. FL_12_CCxCD 3-scFc Bispecific HLE molecule qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks yrtslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirnd lgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgcg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntayIqmnnlktedtavyycv rhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellgg psvf1fppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltv dksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckv snkal papiektiskakgqprepqvytlppsreem tknqvsItclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 506. FL_13xCD3- VH CDR1 narmgvs

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scFc 507. FL_13xCD3scFc VH CDR2 liywnddkryspslks 508. FL_13xCD3scFc VH CDR3 mvgygsgwyayfdy 509. FL_13xCD3scFc VL CDR1 rasqgirndlg 510. FL_13xCD3scFc VL CDR2 aasslqs 511. FL_13xCD3scFc VL CDR3 Iqhnsyplt 512. FL_13xCD3scFc VH qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkalewlaliywnddkr yspslksrltitkdtsknqvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtlv tvss 513. FL_13xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqgir ndlgwyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgggtkveik 514. FL_13xCD3scFc scFv qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkalewlaliywnddkr yspslksrltitkdtsknqvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasq girndlgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiks 515. FL_13xCD3scFc Bispecific molecule qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkalewlaliywnddkr yspslksrltitkdtsknqvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasq girndlgwyqqkpg

- 225 043309

kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywayw gqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 516. FL_13xCD3scFc Bispecific HLE molecule qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkalewlaliywnddkr yspslksrltitkdtsknqvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssi sasvgdrvtitcrasqg irndlgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycv rhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIgg psvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvd ksrwqqgnvfscsvmhealhnh

- 226 043309

ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceegygs tyrcvsvltvlhgdwlngkeykckvsnkal papiektiskakggprepgvytl ppsreem tkngvsltclvkgfypsdiavewesnggpe nnykttppvldsdgsfflyskitvdksrwg ggnvfscsvmhealhnhytgkslslspgk 517. FL_13_CCxCD 3-scFc VH gvtlkesgpvlvkptgtltltctfsgfsis narmgvswirgppgkclewlaliywnddkr yspslksrltitkdtskngvvltmtnmdpv dtatyycarmvgygsgwyayfdywgggtlv tvss 518. FL_13_CCxCD 3-scFc VL digmtgspsslsasvgdrvtitcrasggir ndlgwyggkpgkapkrliyaasslgsgvps rfsgsgsgteftltisslgpedfatyyclg hnsypltfgcgtkveik 519. FL_13_CCxCD 3-scFc scFv gvtlkesgpvlvkptgtltltctfsgfsis narmgvswirgppgkclewlaliywnddkr yspslksrltitkdtskngvvltmtnmdpv dtatyycarmvgygsgwyayfdywgggtlv tvssggggsggggsggggsdigmtgspssl sasvgdrvtitcrasqgirndl gwyqqkpg kapkrliyaasslgsgvpsrfsgsgsgtef tltisslgpedfatyyclghnsypltfgeg tkveiks 520. FL_13_CCxCD 3-scFc Bispecific molecule gvtlkesgpvlvkptgtltltctfsgfsis narmgvswirgppgkclewlaliywnddkr yspslksrltitkdtskngvvltmtnmdpv dtatyycarmvgygsgwyayfdywgggtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasggirndl gwyggkpg kapkrliyaasslgsgvpsrfsgsgsgtef tltisslgpedfatyyclghnsypltfgeg

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tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkqlewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 521. FL_13_CCxCD З-scFc Bispecific HLE molecule qvtlkesgpvlvkptqtltltctfsqfsis narmgvswirqppgkclewlaliywnddkr yspslksrltitkdtsknqvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasq girndlgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfqggtkitvlggggdktht cppcpapell ggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdqvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkqfyps diavewesngqpennykttppvldsdgsff lysklt vdksrwqqgnvfscsvmhealhnh ytqkslslspgkqgggsggggsgggqsggg gsggggsggggsdkthtcppcpapellggp

- 228 043309

svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvs1tclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyski tvdksrwq qgnvfscsvmhealhnhytqkslslspgk 522. FL_14xCD3scFc VH CDR1 narmgvs 523. FL_14xCD3scFc VH CDR2 hifsndeksystslks 524. FL_14xCD3scFc VH CDR3 ivgygtgwygffdy 525. FL_14xCD3scFc VL CDR1 rtsqgirndlg 526. FL_14xCD3scFc VL CDR2 aasslqs 527. FL_14xCD3scFc VL CDR3 Iqhnsyplt 528. FL_14xCD3scFc VH Qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltmtdmdpe dtatyycarivgygtgwygffdywgqgilv tvss 529. FL_14xCD3scFc VL diqmtqspsslsasvgdrvtitcrtsqgir ndlgwyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgggtkveik 530. FL_14xCD3scFc scFv Qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltmtdmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrtsqgirndl gwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef

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tltisslqpedfatyyclqhnsypltfggg tkveiks 531. FL_14xCD3scFc Bispecific molecule Qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltmtdmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrtsqgirndl gwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgn fgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 532. FL_14xCD3scFc Bispecific HLE molecule Qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltmtdmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrtsqgirndl gwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgn fgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey

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ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtkn qvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwy vdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 533. FL_14_CCxCD 3-scFc VH qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtdmdpe dtatyycarivgygtgwygffdywgqgilv tvss 534. FL_14_CCxCD 3-scFc VL diqmtqspsslsasvgdrvtitcrtsqgir ndlgwyqqkpgkapkrliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgcgtkveik 535. FL_14_CCxCD 3-scFc scFv qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtdmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrtsqgirnd lgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiks

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536. FL_14_CCxCD 3-scFc Bispecific molecule qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtdmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrtsqgirnd lgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntay1qmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 537. FL_14_CCxCD 3-scFc Bispecific HLE molecule qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtdmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrtsqgirnd lgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntay1qmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggps vfIfppkpkdtlmisr

-232043309

tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvm healhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprep qvytlppsreem tknqvs1tclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 538. FL_15xCD3scFc VH CDR1 sygmh 539. FL_15xCD3scFc VH CDR2 visyegsnefyaesvkg 540. FL_15xCD3scFc VH CDR3 ggeitmvrgvigyyyygmdv 541. FL_15xCD3scFc VL CDR1 rasqsissyln 542. FL_15xCD3scFc VL CDR2 aasslqs 543. FL_15xCD3scFc VL CDR3 Iqhnsyplt 544. FL_15xCD3scFc VH qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkglewvavisyegsnefу aesvkgrftisrdnskntlylqmnslraed tavyycarggeitmvrgvigyyyygmdvwg qgttvtvss 545. FL_15xCD3scFc VL diqmtqspsslsasvgdrvtitcrasqsis sylnwyqqkpgkapklliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq

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hnsypltfgggtkveik 546. FL_15xCD3scFc scFv qvqlvesgggvvqpgrsirIscaasgftfs sygmhwvrqapgkglewvavisyegsnefу aesvkgrftisrdnskntlylqmnslraed tavyycarggeitmvrgvigyyyygmdvwg qgttvtvssggggsggggsggggsdiqmtq spsslsasvgdrvtit crasqsissylnwy qqkpgkapklliyaasslqsgvpsrfsgsg sgteftltisslqpedfatyyclqhnsypl tfgggtkveiks 547. FL_15xCD3scFc Bispecific molecule qvqlvesgggvvqpgrsirIscaasgftfs sygmhwvrqapgkglewvavisyegsnefу aesvkgrftisrdnskntlylqmnslraed tavyycarggeitmvrgvigyyyygmdvwg qgttvtvssggggsggggsggggsdiqmtq spsslsasvgdrvtit crasqsissylnwy qqkpgkapklliyaasslqsgvpsrfsgsg sgteftltisslqpedfatyyclqhnsypl tfgggtkveiksggggsevqlvesggglvq pggslklscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlktedtavy ycvrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsllggkaaltlsgvqpe deaeyycvlwysnrwvfgggtkltvl 548. FL_15xCD3scFc Bispecific HLE molecule qvqlvesgggvvqpgrsirIscaasgftfs sygmhwvrqapgkglewvavisyegsnefу aesvkgrftisrdnskntlylqmnslraed tavyycarggeitmvrgvigyyyygmdvwg qgttvtvssggggsggggsggggsdiqmtq spsslsasvgdrvtit crasqsissylnwy qqkpgkapklliyaasslqsgvpsrfsgsg sgteftltisslqpedfatyyclqhnsypl

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tfgggtkveiksggggsevqlvesggglvq pggslklscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlktedtavyycvrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsgsllggkaaltlsgvqpe deaeyycvlwysnrwvfgggtkltvlgggg dkthtcppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygs tyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttppvlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslspgkgggggsggggsggg gsggggsggggsggggsdktht cppcpape llggpsvfIfppkpkdtImisrtpevtcvv vdvshedpevkfnwyvdgvevhnaktkpce eqygstyrcvsvltvlhqdwlngkeykckv snkalpapiektiskakgqprepqvytlpp sreemtknqvsltclvkgfypsdiavewes ngqpennykttppvldsdgsff lyskitvd ksrwqqgnvfscsvmhealhnhytqkslsl spgk 549. FL_15_CCxCD 3-scFc VH qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkclewvavisyegsnefу aesvkgrftisrdnskntlylqmnslraed tavyycarggeitmvrgvigyyyygmdvwg qgttvtvss 550. FL_15_CCxCD 3-scFc VL diqmtqspsslsasvgdrvtitcrasqsis sylnwyqqkpgkapklliyaasslqsgvps rfsgsgsgteftltisslqpedfatyyclq hnsypltfgcgtkveik

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551. FL_15_CCxCD 3-scFc scFv qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkclewvavisyegsnefу aesvkgrftisrdnskntlylqmnslraed tavyycarggeitmvrgvigyyyygmdvwg qgttvtvssggggsggggsggggsdiqmtq spsslsasvgdrvtit crasqsissylnwy qqkpgkapklliyaasslqsgvpsrfsgsg sgteftltisslqpedfatyyclqhnsypl tfgcgtkveiks 552. FL_15_CCxCD 3-scFc Bispecific molecule qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkclewvavisyegsnefу aesvkgrftisrdnskntlylqmnslraed tavyycarggeitmvrgvigyyyygmdvwg qgttvtvssggggsggggsggggsdiqmtq spsslsasvgdrvtit crasqsissylnwy qqkpgkapklliyaasslqsgvpsrfsgsg sgteftltisslqpedfatyyclqhnsypl tfgcgtkveiksggggsevqlvesggglvq pggslklscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlktedta vyycvrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsllggkaaltlsgvqpe deaeyycvlwysnrwvfgggtkltvl 553. FL_15_CCxCD 3-scFc Bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkclewvavisyegsnefу aesvkgrftisrdnskntlylqmnslraed tavyycarggeitmvrgvigyyyygmdvwg qgttvtvssggggsggggsggggsdiqmtq spsslsasvgdrvtit crasqsissylnwy qqkpgkapklliyaasslqsgvpsrfsgsg sgteftltisslqpedfatyyclqhnsypl tfgcgtkveiksggggsevqlvesggglvq

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pggslklscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlktedtavyycvrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgq aprgliggt kflapgtparfsgsllggkaaltlsgvqpe deaeyycvlwysnrwvfgggtkltvlgggg dkthtcppcpape11ggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygstyrcvsvltvlh qdwlngkeykckv snkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttppvlds dgsfflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslspgkggggsggggsggg gsggggsggggsggggsdkthtcppcpape llggpsvfIfppkpkdt lmisrtpevtcvv vdvshedpevkfnwyvdgvevhnaktkpce eqygstyrcvsvltvlhqdwlngkeykckv snkalpapiektiskakgqprepqvytlpp sreemtknqvsltclvkgfypsdiavewes ngqpennykttppvidsdgsfflyskitvd ksrwqqgnvfscsvmhe aIhnhytqkslsl spgk FL_lxCD3- Bispecific qvtlkesgpalvkptetltltctvsgfsis narmgvswirqppgkalewlanifsndeks ystslksrltiskgtsksqvvltmtnmdpe dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl 554. scFc_delGK molecule HLE sasvgdrvtitcrasqgirndlgwyqqkpg kapqrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv

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arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknq vsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhn aktkpceeqygsty rcvsvltvlhqdwlnqkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk FL_l_CCxCD3 Bispecific qvtlkesgpalvkptetltltctvsgfsis narmgvswirqppgkclewlanifsndeks ystslksrltiskgtsksqvvltmtnmdpe dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvqdrvtitcrasqgirndlgw yqqkpg 555. -scFc_delGK molecule HLE kapqrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy

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isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIggpsvfIfpp kpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqq gnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakg qprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmheaIhnhytqkslslspgk 556. FL_2xCD3scFc_delGK Bispecific HLE molecule qvtlkesgptlvkptetltltctlsgfsin narmgvswirqppgkalewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygsgwygffdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndl gwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga

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vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvgpedeaey ycvlwysnrwvfgggtkitvlggggdktht cppcpapellggpsvfIfppkpkdtImisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceegygstyrc vsvltvlhgdwln gkeykckvsnkalpapiektiskakgqpre pgvytlppsreemtkngvsltclvkgfyps diavewesnggpennykttppvldsdgsff lyskltvdksrwgggnvfscsvmhealhnh ytgkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcp apellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceegygsty rcvsvltvlhgdwlngkeykckvsnkalpa piektiskakggprepgvytlppsreemtk ngvsltclvkgfypsdiavewesnggpenn ykttppvldsdgsfflyskit vdksrwggg nvfscsvmhealhnhytgkslslspgk 557. FL_2_CCxCD ³ -scFc_delGK Bispecific HLE molecule gvtlkesgptlvkptetltltctlsgfsin narmgvswirgppgkclewlahifsndeks ystslknrltiskdssktgvvltmtnvdpv dtatyycarivgygsgwygffdywgggtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlgw ygqkpg kapkrliyaastlgsgvpsrfsgsgsgtef tltisslgpedfatyyclghnsypltfgeg tkveiksggggsevglvesggglvgpggsl klscaasgftfnkyamnwvrgapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylgmnnlktedtavyycvrhgnfgn sy isywaywgggtlvtvssggggsggggsggg gsgtvvtgepsltvspggtvtltcgsstga vtsgnypnwvggkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvgpedeaey

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ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvf1fppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtk nqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fifppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgve vhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 558. FL_3xCD3scFc_delGK Bispecific HLE molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgktlewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsqwygyfdywgqqtlv tvssqgggsggggsgqggsdiqmtqspssl sasvqdrvtitcrasqdirndl gwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsv f1fppkpkdtlmisr

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tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsItclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvm healhnh ytqkslslspggggsqgggsggggsgqggs ggggsggggsdkthtcppcpapellgqpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqyqsty rcvsvltvlhqdwlnqkeykckvsnkalpa piektiskakgqprep qvytlppsreemtk nqvsItclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 559. Еь_ ³ _ССхСБЭ -scFc_delGK Bispecific HLE molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgkclewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsqwygyfdywgqqtlv tvssqgggsggggsgqggsdiqmtqspssl sasvqdrvtitcrasqdirndl gwyqqkpg kapkrliyaastlqsqvpsrfsgsgsqtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkitvlggggdktht cppcpapellggpsv fIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln

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gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfpp kpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqq g nvfscsvmheaIhnhytqkslslspgk 560. FL_4xCD3scFc_delGK Bispecific HLE molecule qvtlkesgpalvkptetltltctlsgfsin nakmgvswirqppgkalewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirddl gwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntay1qmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggps vfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps

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diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqy gsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 561. FL_4_CCxCD3 -scFc_delGK Bispecific HLE molecule qvtlkesgpalvkptetltltctlsgfsin nakmgvswirqppgkclewlahifsndeks ystslksrltiskdtskgqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirddl gwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgcg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggps vfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdks rwqqgnvfscsvmhealhnh

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ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsre emtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 562. FL_5xCD3scFc_delGK Bispecific HLE molecule qvtlkesgpvlvkptetltltctvsgfsir narmavswirqppgktlewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssv sasvgdrvtitcrasqdiryd lawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnfypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgn fgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvf Ifppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrw qqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv

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f1fppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvd ksrwqqg nvfscsvmhealhnhytqkslslspgk 563. FL_5_CCxCD ³ -scFc_delGK Bispecific HLE molecule qvtlkesgpvlvkptetltltctvsgfsir narmavswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwygyfdywgqgtlv tvssggggsggggsggggsdiqmtqspssv sasvgdrvtitcrasqdiryd lawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnfypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgn fgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpape11ggpsv fIfppkpkdtImisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksr wqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty

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rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 564. FL_6xCD3scFc_delGK Bispecific HLE molecule qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks fstslknrltis kdt s ks qvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtqv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcra sqsissylnwyqqkpg kapklliyaasslqsgvpsrfsgsgsgtdf tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpape llggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytIppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lysklt vdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkal pa piektiskakgqprepqvytlppsreemtk

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nqvsItclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 565. ^FL _6_ ^CCxCD3 -scFc_delGK Bispecific HLE molecule qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks fstslknrltis kdt s ks qvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtqv tvssggggsggggsggggsdiqmtqspssi sasvgdrvtitcras qsissylnwyqqkpg kapklliyaasslqsgvpsrfsgsgsgtdf tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelI ggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltv dksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsItclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg

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nvfscsvmhealhnhytqkslslspgk 566. FL_7xCD3scFc_delGK Bispecific HLE molecule qvtlkesgptlvkptetltltctvsgfsin narmgvswirqppgkalewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygtgwfgyfdywgqgtqv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdi rtdlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnrypltfggg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrh gnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpape11ggps vfIfppkpkdtImisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdks rwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa pie ktiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 567. FL_7_CCxCD3 Bispecify qvtlkesgptlvkptetltltctvsgfsin

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-scFc_delGK cheskaya molecule HLE narmgvswirqppgkclewlahifsndeks ystslknrltiskdssktqvvltmtnvdpv dtatyycarivgygtgwfgyfdywgqgtqv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdirtdlawyqqkpg kapkrliyaasslqsgv psrfsgsgsgtef tltisslqpedfatyyclqhnrypltfgcg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggs ggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvd vshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsf f lyskitvdksrwqqgnvfscsvmhealhnh ytqks lslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqv sItclvkgfypsdiavewesngqpenn ykttppvldsdgs fflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 568. FL_8xCD3scFc_delGK Bispecific molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgktlewlahifsndeks ystslksrltis kdt s ks qvvltmtnmdp e

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HLE dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqgirndlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggs l klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntayIqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgligg tkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvf1fppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsn kalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrt pevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvs1tclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsv mhealhnhytqkslslspgk 569. FL_8_CCxCD ³ -scFc_delGK Bispecific HLE molecule qvtlkesgpalvkptetltltctlsgfsin narmavswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtnmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl

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sasvgdrvtitcrasqgirndlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgcg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl ggggdktht cppcpapellggpsvfifppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennyktt ppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhq dwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 570. FL_9xCD3scFc_delGK Bispecific HLE molecule qvtlkesgptlvkptetltltctfsgfsir yarmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqd irndlawyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef

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tltisslgpedfatyyclghnsypltfggg tkleiksggggsevglvesgggglvgpggsl klscaasgftfnkyamnwvrgapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylgmnnlktedtavyycvrhgnfgnsy isywaywgggtlvtvssggggsggggsggg gsgtv vtgepsltvspggtvtltcgsstga vtsgnypnwvggkpggaprgliggtkflap gtparfsgsllggkaaltlsgvgpedeaey ycvlwysnrwvfgggtkitvlggggdktht cppcpapellggpsvfIfppkpkdtImisr tpevtcvvvdvshedpevkfnwyvdgve vh naktkpceegygstyrcvsvltvlhgdwln gkeykckvsnkalpapiektiskakggpre pgvytlppsreemtkngvsltclvkgfyps diavewesnggpennykttppvldsdgsff lyskltvdksrwgggnvfscsvmhealhnh ytgkslslspggggsggggsggggsggggs gg ggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytgkslslspgk 571. FL_9_CCxCD ³ -scFc_delGK Bispecific HLE molecule qvtlkesgptlvkptetltltctfsgfsir yarmgvswirgppgkclewlahifsndeks ystslksrltiskdtsksgvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdigmtgspssl sasvgdrvtitcrasqdir ndlawyqqkpg kapkrliyaasslgsgvpsrfsgsgsgtef tltisslgpedfatyyclghnsypltfgeg tkleiksggggsevglvesggglvgpggsl

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klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggt kflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkitvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkal papiektiskakgqpre pqvytlppsreemtknqvsItclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsqgggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpev tcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlnqkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsItclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhe aIhnhytqkslslspgk 572. FL_10xCD3scFc_delGK Bispecific HLE molecule qvtlkesgpvlvkptetltltctvsgfsfr narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssqwsgafdiwgqgtmv tvssggggsggggsgqggsdiqmtqspssl sasvgdrvtitcrasq dirddlgwyqqkpg napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk

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ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltv lggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykt tppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthteppepapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqd wlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk FL_10_CCxCD Bispecific qvtlkesgpvlvkptetltltctvsgfsfr narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdi rddlgwyqqkpg 573. 3- scFc_delGK molecule HLE napkrliygastlqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkvdiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isyway wgqgtlvtvssggggsggggsggg

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gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpev kfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgggg sggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkg fypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 574. FL_llxCD3scFc_delGK Bispecific HLE molecule qvtlkesgpalvkptetltltctvsgfsfr narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssgwsgafdiwgqgtmv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqdigy dlgwyqqkpg kapkrliyaastlqsgvpsrfsgsgsgtef tliisslqpedfatyyclqhnsfpwtfgqg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavy ycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap

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gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkitvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapie ktiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdqsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsqgggsggggsgqggs ggggsggggsdkthtcppcpapellgqpsv fIfppkpkdtlmisrtp evtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqyqsty rcvsvltvlhqdwlnqkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsv mhealhnhytqkslslspgk 575. FL_ll_CCxCD 3- scFc_delGK Bispecific HLE molecule qvtlkesgpalvkptetltltctvsgfsfr narmqvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltltnmdpv dtatyfcarmpeyssqwsgafdiwgqqtmv tvssqgggsggggsgqggsdiqmtqspssl sasvgdrvtitcrasqdi gydlgwyqqkpg kapkrliyaastlqsqvpsrfsgsgsqtef tliisslqpedfatyyclqhnsfpwtfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavy ycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkitvlggggdktht

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cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsd gsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeyk ckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 576. FL_12xCD3scFc_delGK Bispecific HLE molecule qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks yrtslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsqwyayfdywgqqtlv tvssqgggsggggsgqggsdiqmtqspssl sasvqdrvtitcrasqgir ndlgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntay1qmnnlktedtavyycv rhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellgg psvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh

-258 043309

naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpen n ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk FL_12_CCxCD Bispecific qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks yrtslksrltiskdtsksqvvltmtnmdpv dtatyycarivgygsgwyayfdywgqgtlv tvssqgggsggggsgqggsdiqmtqspssl sasvqdrvtitcrasqgir ndlgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv 577. 3- scFc_delGK molecule HLE arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre

-259043309

pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdv shed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvs1tclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqksls lspgk 578. FL_13xCD3scFc_delGK Bispecific HLE molecule qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkalewlaliywnddkr yspslksrltitkdtsknqvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasq girndlgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapell ggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff

-260043309

lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykck vsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 579. FL_13_CCxCD 3- scFc_delGK Bispecific HLE molecule qvtlkesgpvlvkptqtltltctfsgfsis narmgvswirqppgkclewlaliywnddkr yspslksrltitkdtsknqvvltmtnmdpv dtatyycarmvgygsgwyayfdywgqgtlv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasq girndlgwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpape1 1ggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lysklt vdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs

- 261 043309

ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngq penn ykttppvldsdgsfflyskltvdksrwqqg nvfscsvmhealhnhytqkslslspgk 580. FL_14xCD3scFc_delGK Bispecific HLE molecule Qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkalewlahifsndeks ystslksrltiskdtsksqvvltmtdmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrtsqgirndl gwyqqkpg kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgn fgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIggpsvf Ifppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrw qqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed

- 262 043309

pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskltvdksrwqqg nvfscsvmhealhnhytqkslsl spgk 581. FL_14_CCxCD 3- scFc_delGK Bispecific HLE molecule qvtlkesgpalvkptqtltltctfsgfsis narmgvswirqppgkclewlahifsndeks ystslksrltiskdtsksqvvltmtdmdpe dtatyycarivgygtgwygffdywgqgilv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrtsqqirnd lgwyqqkpq kapkrliyaasslqsgvpsrfsgsgsgtef tltisslqpedfatyyclqhnsypltfgcg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfqggtkitvlggggdktht cppcpapellggps vf1fppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvd ksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa

- 263 043309

piektiskakgqprepqvytlppsreemtk nqvsItclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 582. FL_15xCD3scFc_delGK Bispecific HLE molecule qvqlvesgggvvqpgrsirIscaasgftfs sygmhwvrqapgkglewvavisyegsnefу aesvkgrftisrdnskntlylqmnslraed tavyycarggeitmvrgvigyyyygmdvwg qgttvtvssggggsggggsggggsdiqmtq spsslsasvgdrvtit crasqsissylnwy qqkpgkapklliyaasslqsgvpsrfsgsg sgteftltisslqpedfatyyclqhnsypl tfgggtkveIksgggqsevqlvesggglvq pggs1klscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlkted tavyycvrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsllggkaaltlsgvqpe deaeyycvlwysnrwvfgggtkitvlgggg dktht cppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttppvlds dgs fflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslspggggsggggsggggs ggggsggggsggggsdkthtcppcpapell ggpsvfIfppkpkdtlmisrtpevtcvvvd vshedpevkfnwyvdgvevhnaktkpceeq ygstyrcvsvltvlhqdwlngkeykckvs n kalpapiektiskakgqprepqvytlppsr eemtknqvsItclvkqfypsdiavewesng

- 264 043309

qpennykttppvldsdgsfflyskitvdks rwqqgnvfscsvmhealhnhytqkslslsp gk 583. FL_15_CCxCD 3- scFc_delGK Bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkclewvavisyegsnefу aesvkgrftisrdnskntlylqmnslraed tavyycarggeitmvrgvigyyyygmdvwg qgttvtvssggggsggggsggggsdiqmtq spsslsasvgdrvtit crasqsissylnwy qqkpgkapklliyaasslqsgvpsrfsgsg sgteftltisslqpedfatyyclqhnsypl tfgcgtkveiksggggsevqlvesggglvq pggs1klscaasgftfnkyamnwvrqapgk glewvarirskynnyatyyadsvkdrftis rddskntaylqmnnlkted tavyycvrhgn fgnsyisywaywgqgtlvtvssggggsggg gsggggsqtvvtqepsltvspggtvtltcg sstgavtsgnypnwvqqkpgqaprgliggt kflapgtparfsllggkaaltlsgvqpe deaeyycvlwysnrwvfgggtkltvlgggg dktht cppcpapellggpsvfIfppkpkdt Imisrtpevtcvvvdvshedpevkfnwyvd gvevhnaktkpceeqygstyrcvsvltvlh qdwlngkeykckvsnkalpapiektiskak gqprepqvytlppsreemtknqvsltclvk gfypsdiavewesngqpennykttppvlds dgs fflyskitvdksrwqqgnvfscsvmhe alhnhytqkslslspggggsggggsggggs ggggsggggsggggsdkthtcppcpapell ggpsvfIfppkpkdtlmisrtpevtcvvvd vshedpevkfnwyvdgvevhnaktkpceeq ygstyrcvsvltvlhqdwlngkeykckvs n kalpapiektiskakgqprepqvytlppsr eemtknqvsItclvkgfypsdiavewesng qpennykttppvldsdgsfflyskitvdks

- 265 043309

rwqqgnvfscsvmhealhnhytqkslslsp gk 584. CD70_l_CCxC D3-scFc VH CDR1 Syams 585. CD70_l_CCxC D3-scFc VH CDR2 visgsggrpnyaesvkg 586. CD70_l_CCxC D3-scFc VH CDR3 vdysnylffdy 587. CD70_l_CCxC D3-scFc VL CDR1 ragqsvrssylg 588. CD70_l_CCxC D3-scFc VL CDR2 gassrat 589. CD70_l_CCxC D3-scFc VL CDR3 qqygysppt 590. CD70_l_CCxC D3-scFc VH evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvsvisgsggrpny aesvkgrftisrdnskntlylqmnslrded tavyycakvdysnylffdywgqgtlvtvss 591. CD70_l_CCxC D3-scFc VL eivltqspgtlslspgegatlscragqsvr ssylgwyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygyspptfgcgtkleik 592. CD70_l_CCxC D3-scFc scFv evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvsvisgsggrpny aesvkgrftisrdnskntlylqmnslrded tavyycakvdysnylffdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp gegatlscragqsvrssylgwyqqk pgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspptfgcgtkl eik 593. CD70_l_CCxC D3-scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvsvisgsggrpny aesvkgrftisrdnskntlylqmnslrded tavyycakvdysnylffdywgqgtlvtvss

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ggggsggggsggggseivltqspgtlslsp gegatlscragqsvrssylgwyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspptfgcgtkl eiksggggsevqlvesgggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari r skynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyyc v Iwysnrwvfgggtkltvl 594. CD70_l_CCxC D3-scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsvisgsggrpny aesvkgrftisrdnskntlylqmnslrded tavyycakvdysnylffdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp gegatlscragqsvrssylgwyqqkp gqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspptfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkd tlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytIppsreemtknqvsltclvkgfypsdia

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vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpcee qygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmheaIhnhytqkslslspgk 595. CD70_lxCD3scFc VH evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsvisgsggrpny aesvkgrftisrdnskntlylqmnslrded tavyycakvdysnylffdywgqgtlvtvss 596. CD70_lxCD3scFc VL eivltqspgtlslspgegatlscragqsvr ssylgwyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygyspptfgggtkleik 597. CD70_lxCD3scFc scFv evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsvisgsggrpny aesvkgrftisrdnskntlylqmnslrded tavyycakvdysnylffdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp gegatlscragqsvrssylgwyqqk pgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspptfgggtkl eik 598. CD70_lxCD3scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsvisgsggrpny aesvkgrftisrdnskntlylqmnslrded tavyycakvdysnylffdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp gegatlscragqsvrssylgwyqqk pgqap rlliygassratgipdrfsgsgsgtdftit

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isrlepedfavyycqqygyspptfgggtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtq epsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 599. CD70_lxCD3scFc bispecific HLE molecule evqllesggglvqpggsIriscaasgftfs syamswvrqapgkglewvsvisgsggrpny aesvkgrftisrdnskntlylqmnslrded tavyycakvdysnylffdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp gegatlscragqsvrssylgwyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspptfgggtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtI misrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfsc svmhealhnhytq kslslspgKggggsggggsggggsggggsg

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gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesng qpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 600. CD70_2_CCxC D3-scFc VH CDR1 iyams 601. CD70_2_CCxC D3-scFc VH CDR2 aisgsggstfyaesvkg 602. CD70_2_CCxC D3-scFc VH CDR3 hdysnypyfdy 603. CD70_2_CCxC D3-scFc VL CDR1 rasqsvrssyla 604. CD70_2_CCxC D3-scFc VL CDR2 gassrat 605. CD70_2_CCxC D3-scFc VL CDR3 qqygdlpft 606. CD70_2_CCxC D3-scFc VH evqllesggglvqpggslklscaasgftfs iyamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyуcakhdysnypyfdywgqgtlvtvss 607. CD70_2_CCxC D3-scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgcgtkleik 608. CD70_2_CCxC D3-scFc scFv evqllesggglvqpggslklscaasgftfs iyamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyуcakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap r lliygassratgipdrfsgsgsgtdftit

- 270 043309

isrlepedfavyycqqygdlpftfgcgtkl elk 609. CD70_ ² _CCxC D3-scFc bispecific molecule evqllesggglvqpggslklscaasgftfs iyamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap r lliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 610. CD70_ ² _CCxC D3-scFc bispecific HLE molecule evqllesggglvqpggslklscaasgftfs iyamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap r lliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv

- 271 043309

Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvs ltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvev hnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 611. CD70_2xCD3scFc VH evqllesggglvqpggslklscaasgftfs iyamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 612. CD70_2xCD3scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgpgtkleik 613. CD70_2xCD3scFc scFv evqllesggglvqpggslklscaasgftfs iyamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap r lliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkl elk 614. CD70_2xCD3- bispecifically evqllesggglvqpggslklscaasgftfs

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scFc cheskaya molecule iyamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdft it isrlepedfavyycqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tv vtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 615. CD70_2xCD3scFc bispecific HLE molecule evqllesggglvqpggslklscaasgftfs iyamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap r lliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtl misrtpe vtcvvvdvshedpevkfnwyvdgvevhnak

-273 043309

tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggs ggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiave wesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 616. CD70_3_CCxC D3-scFc VH CDR1 Syams 617. CD70_3_CCxC D3-scFc VH CDR2 aisgsggrtfyaesveg 618. CD70_3_CCxC D3-scFc VH CDR3 hdysnypyfdy 619. CD70_3_CCxC D3-scFc VL CDR1 rasqsvrssyla 620. CD70_3_CCxC D3-scFc VL CDR2 gassrat 621. CD70_3_CCxC D3-scFc VL CDR3 qqygsspft 622. CD70_3_CCxC D3-scFc VH evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlfIqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 623. CD70_3_CCxC D3-scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygsspftfgcgtkleik 624. CD70_3_CCxC scFv evqllesgggmvqpggslrlscaasgftfs

- 274 043309

D3-scFc syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlfIqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdft it isrlepedfavyycqqygsspftfgcgtkl elk 625. CD70_3_CCxC D3-scFc bispecifically ical molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlfIqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 626. CD70_3_CCxC D3-scFc bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlfIqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari

- 275 043309

rskynnyatyyadsvkdrftisrddsknta ylgmnnlktedtavyycvrhgnfgnsyisy waywgggtlvtvssggggsggggsggggsg tvvtgepsltvspggtvtltcgsstgavts gnypnwvggkpggaprgliggtkflapgtp arfsgsllggkaaltlsgvgpedeaeyycv I wysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceegygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakggprepqv ytlppsreemtkngvsltclvkgf ypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwgggnvfscsvmhealhnhytg kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpce egygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakggprepgvytlppsreemtkn gvsItclvkgfypsdiavewesnggpenny kttppvldsdgsfflyskitvdksrwgggn vfscsvmhealhnhytgkslslspgk 627. CD70_3xCD3scFc VH evqllesgggmvqpggslrlscaasgftfs syamswvrgapgkglewvsaisgsggrtfу aesvegrftisrdnskntlfIgmnslraed tavyycakhdysnypyfdywgqgtlvtvss 628. CD70_3xCD3scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyggkpggaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycg gygsspftfgpgtkleik 629. CD70_3xCD3scFc scFv evgllesgggmvgpggslrlscaasgftfs syamswvrgapgkglewvsaisgsggrtfу aesvegrftisrdnskntlfIgmnslraed tavyycakhdysnypyfdywgggtlvtvss

- 276 043309

ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkl elk 630. CD70_3xCD3scFc bispecific molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlfIqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkl eiksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 631. CD70_3xCD3scFc bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlfIqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkl eiksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq

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tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfn wyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKgggg sggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltcl vkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmheaIhnhytqkslslspgk 632. CD70_4_CCxC D3-scFc VH CDR1 Syams 633. CD70_4_CCxC D3-scFc VH CDR2 aisgsggrtfyaesveg 634. CD70_4_CCxC D3-scFc VH CDR3 hdysnypyfdy 635. CD70_4_CCxC D3-scFc VL CDR1 rasqsirssyla 636. CD70_4_CCxC D3-scFc VL CDR2 gassrat 637. CD70_4_CCxC D3-scFc VL CDR3 qqygdlpft 638. CD70_4_CCxC D3-scFc VH evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed

- 278 043309

tavyycakhdysnypyfdywgqgtlvtvss 639. CD70_4_CCxC D3-scFc VL eivltqspgtlslspgeratlscrasqsir ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgcgtkleik 640. CD70_4_CCxC D3-scFc scFv evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eik 641. CD70_4_CCxC D3-scFc bispecifically ical molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv iwysnrwvfgggtkltvl 642. CD70_4_CCxC D3-scFc bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss

- 279 043309

ggggsggggsggggseivltqspgtlslsp geratlscrasqsirssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eiksggggsevqlvesgggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari r skynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyyc v Iwysnrwvfgggtkitvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsIt clvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf 1fppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgve vhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 643. CD70_4xCD3scFc VH EvqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 644. CD70_4xCD3scFc VL Eivltqspgtlslspgeratlscrasqsir ssylawyqqkpgqaprlliygassratgip

- 280 043309

drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgpgtkleik 645. CD70_4xCD3scFc scFv Evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkl elk 646. CD70_4xCD3scFc bispecifically ical molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 647. CD70_4xCD3scFc bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit

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isrlepedfavyycqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tv vtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyv dgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utIppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsgggg sggggsggggsg gggsggggsdkthteppepapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfyps diavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 648. CD70_5_CCxC D3-scFc VH CDR1 Syams 649. CD70_5_CCxC D3-scFc VH CDR2 Aisgsggrthyaesvkg 650. CD70_5_CCxC D3-scFc VH CDR3 hdysnypyfdy 651. CD70_5_CCxC D3-scFc VL CDR1 Rasqsvrssyla 652. CD70_5_CCxC VL CDR2 gassrat

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D3-scFc 653. CD70_5_CCxC D3-scFc VL CDR3 Qqygsspft 654. CD70_5_CCxC D3-scFc VH EvqllesggglvqsggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 655. CD70_5_CCxC D3-scFc VL Eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygsspftfgcgtkleik 656. CD70_5_CCxC D3-scFc scFv EvqllesggglvqsgqslrIscaasgftfs syamswvrqapgkclewvsaisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkl eik 657. CD70_5_CCxC D3-scFc bispecific molecule evqllesggglvqsggslriscaasgftfs syamswvrqapgkclewvsaisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap r lliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqg tlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp

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arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 658. CD70_5_CCxC D3-scFc bispecific HLE molecule evqllesggglvqsggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmis rtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsv mhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepq vytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk

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659. CD70_5xCD3scFc VH Evqllesggglvqsggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 660. CD70_5xCD3scFc VL Eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygsspftfgpgtkleik 661. CD70_5xCD3scFc scFv Evqllesggglvqsggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkl eik 662. CD70_5xCD3scFc bispecific molecule evqllesggglvqsggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 663. CD70_5xCD3- bispecifically evqllesggglvqsggslrlscaasgftfs

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scFc cheskaya HLE molecule syamswvrqapgkglewvsaisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdft it isrlepedfavyycqqygsspftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvt qepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkpkdtImisrtpe vtcvvvdvshedpevkfnwyvd gvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsgggg sggggsggggsg gggsggggsdkthtcppcpape11ggpsvf IfppkpkdtImisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkg fypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 664. CD70_6_CCxC D3-scFc VH CDR1 Syams 665. CD70_6_CCxC VH CDR2 lisgsggrthyaesvkg

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D3-scFc 666. CD70_6_CCxC D3-scFc VH CDR3 hdysnypyfdy 667. CD70_6_CCxC D3-scFc VL CDR1 rasqsvrstyla 668. CD70_6_CCxC D3-scFc VL CDR2 dassrat 669. CD70_6_CCxC D3-scFc VL CDR3 qqygssppt 670. CD70_6_CCxC D3-scFc VH evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvslisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 671. CD70_6_CCxC D3-scFc VL eivltqspgtlslspgeratlscrasqsvr stylawyqqkpgqaprlliydassratgip drfsgsgsgtdftltisrlepedfavyfcq qygsspptfgcgtkleik 672. CD70_6_CCxC D3-scFc scFv evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvslisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgq ap rlliydassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgcgtkl eik 673. CD70_6_CCxC D3-scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvslisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgq ap rlliydassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgcgtkl eiksggggsevqlvesggglvqpggslkls

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caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapg tp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkitvl 674. CD70_6_CCxC D3-scFc bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvslisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggqgsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgq ap rlliydassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkitvlqgggdkthtcpp cpapellggpsvfIfppkpkdtl misrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsItclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscs vmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf 1fppkpkdtlmisrtpevtcvvvdvshedp

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evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspg k 675. CD70_6xCD3scFc VH evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvslisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 676. CD70_6xCD3scFc VL eivltqspgtlslspgeratlscrasqsvr stylawyqqkpgqaprlliydassratgip drfsgsgsgtdftltisrlepedfavyfcq qygsspptfgggtkleik 677. CD70_6xCD3scFc scFv evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvslisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgqap rlliydassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgggtkl eik 678. CD70_6xCD3scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvslisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgqap rlliydassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgggtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta y1qmnnlktedtavyycvrhgnfgnsyisy

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waywgqgtlvtvssggqgsggggsgqggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprqliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 679. CD70_6xCD3scFc bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvslisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgq ap rlliydassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgggtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqg tlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprqliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmis rtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscs vmhealhnhytq kslslspgKgggqsggqgsggggsgqggsq gggsggggsdkthtcppcpapellgqpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqyqstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakg qprepqvytlppsreemtkn

- 290 043309

qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 680. CD70_7_CCxC D3-scFc VH CDR1 tyams 681. CD70_7_CCxC D3-scFc VH CDR2 aisgsggstfyaesvkg 682. CD70_7_CCxC D3-scFc VH CDR3 hdysnypyfdy 683. CD70_7_CCxC D3-scFc VL CDR1 rasqsvrssyla 684. CD70_7_CCxC D3-scFc VL CDR2 gassrat 685. CD70_7_CCxC D3-scFc VL CDR3 qqygdlpft 686. CD70_7_CCxC D3-scFc VH evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlslqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 687. CD70_7_CCxC D3-scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgcgtkleik 688. CD70_7_CCxC D3-scFc scFv evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlslqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eik 689. CD70_7_CCxC D3-scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlslqmnslraed

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tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggs lkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflap gtp arfsgsllggkaaltlsgvqpedeaeyycv iwysnrwvfgggtkltvl 690. CD70_7_CCxC D3-scFc bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs tyamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntisIqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfifppkpk dtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv

-292043309

ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvd vshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslsl spgk 691. CD70_7xCD3scFc VH evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlslqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 692. CD70_7xCD3scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgpgtkleik 693. CD70_7xCD3scFc scFv evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlslqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkl eik 694. CD70_7xCD3scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlslqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap

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rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 695. CD70_7xCD3scFc bispecific HLE molecule evqllesggglvqpggsIriscaasgftfs tyamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlslqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdt lmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utIppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfsc svmhealhnhytq

- 294 043309

kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsre emtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 696. CD70_8_CCxC D3-scFc VH CDR1 tyams 697. CD70_8_CCxC D3-scFc VH CDR2 aisgsggrtfyaesveg 698. CD70_8_CCxC D3-scFc VH CDR3 hdysnypyfdy 699. CD70_8_CCxC D3-scFc VL CDR1 rasqsvrstyla 700. CD70_8_CCxC D3-scFc VL CDR2 gassrat 701. CD70_8_CCxC D3-scFc VL CDR3 qqygdlpft 702. CD70_8_CCxC D3-scFc VH evqllesgggmvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 703. CD70_8_CCxC D3-scFc VL eivltqspgtlslspgeratlscrasqsvr stylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyscq qygdlpftfgcgtkleik 704. CD70_8_CCxC D3-scFc scFv evqllesgggmvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgq ap

- 295 043309

rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgcgtkl eik 705. CD70_8_CCxC D3-scFc bispecific molecule evqllesgggmvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 706. CD70_8_CCxC D3-scFc bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp

- 296 043309

arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiska kgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmheaIhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapelIggpsvf Ifppkpkdtlmisrtpev tcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvs1tclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmheal hnhytqkslslspgk 707. CD70_8xCD3scFc VH evqllesgggmvqpggslrlscaasgftfs tyamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 708. CD70_8xCD3scFc VL eivltqspgtlslspgeratlscrasqsvr stylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyscq qygdlpftfgpgtkleik 709. CD70_8xCD3scFc scFv evqllesgggmvqpggslrlscaasgftfs tyamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgpgtkl eik

- 297 043309

710. CD70_8xCD3scFc bispecific molecule evqllesgggmvqpggslrIscaasgftfs tyamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 711. CD70_8xCD3scFc bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs tyamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkpk dtImisrtpe

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vtcvvvdvshedpevkfnwyvdgvevhnak tkpceegygstyrcvsvltvlhgdwlngke ykckvsnkalpapiektiskakggprepgv utlppsreemtkngvsltclvkgfypsdia vewesnggpennykttppvldsdgsfflys kltvdksrwgggnvfscsvmhealhn hytg kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceegygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlpps reemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytgkslslspgk 712. CD70_9_CCxC D3-scFc VH CDR1 Syams 713. CD70_9_CCxC D3-scFc VH CDR2 aisgsggytyyaesvkg 714. CD70_9_CCxC D3-scFc VH CDR3 hdysnypyfdy 715. CD70_9_CCxC D3-scFc VL CDR1 rasqsvrsnyla 716. CD70_9_CCxC D3-scFc VL CDR2 gassrat 717. CD70_9_CCxC D3-scFc VL CDR3 ggygdlpft 718. CD70_9_CCxC D3-scFc VH evgllesggglvgpggslrlscaasgftfs syamswvrgapgkclewvsaisgsggytyy aesvkgrftisrdnskntlylgmnslraed tavyycakhdysnypyfdywgggtlvtvss 719. CD70_9_CCxC D3-scFc VL eivltgspgtlslspgeratlscrasgsvr snylawyggkpggaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycg gygdlpftfgcgtkveik

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720. CD70_9_CCxC D3-scFc scFv evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggytyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv elk 721. CD70_9_CCxC D3-scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggytyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta uIqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 722. CD70_9_CCxC D3-scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggytyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls

- 300 043309

caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapg tp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektis kakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpev tcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhn hytqkslslspgk 723. CD70_9xCD3scFc VH evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggytyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 724. CD70_9xCD3scFc VL eivltqspgtlslspgeratlscrasqsvr snylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgpgtkveik 725. CD70_9xCD3scFc scFv evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggytyy aesvkgrftisrdnskntlylqmnslraed

- 301 043309

tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv elk 726. CD70_9xCD3scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggytyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 727. CD70_9xCD3scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggytyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy

- 302 043309

waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkp kdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgn vfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapelIggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiska kgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 728. CD70_10_CCx CD3-scFc VH CDR1 Syams 729. CD70_10_CCx CD3-scFc VH CDR2 aisgsggstfyaesvkg 730. CD70_10_CCx CD3-scFc VH CDR3 hdysnypyfdy 731. CD70_10_CCx CD3-scFc VL CDR1 rasqsvrssyla 732. CD70_10_CCx CD3-scFc VL CDR2 gassrat 733. CD70_10_CCx CD3-scFc VL CDR3 qqygdlpft 734. CD70_10_CCx CD3-scFc VH evqllesggglaqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggstfу

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aesvkgrftisrdnskntlylqmnslraed tavyfcakhdysnypyfdywgqgtlvtvss 735. CD70_10_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgcgtkveik 736. CD70_10_CCx CD3-scFc scFv evqllesggglaqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyfcakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eik 737. CD70_10_CCx CD3-scFc bispecific molecule evqllesggglaqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyfcakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 738. CD70_10_CCx CD3-scFc bispecifically cheskaya HLE evqllesggglaqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed

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molecule tavyfcakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggs lkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprgliggtkflap gtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiek tiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf 1fppkpkdtImis rtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvm healhnhytqkslslspgk 739. CD70_10xCD3 -scFc VH evqllesggglaqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyfcakhdysnypyfdywgqgtlvtvss 740. CD70_10xCD3 VL eivltqspgtlslspgeratlscrasqsvr

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-scFc ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgpgtkveik 741. CD70_10xCD3 -scFc scFv evqllesggglaqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyfcakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eik 742. CD70_10xCD3 -scFc bispecific molecule evqllesggglaqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyfcakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 743. CD70_10xCD3 -scFc bispecific HLE molecule evqllesggglaqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyfcakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap

- 306 043309

rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkitvlggggdkthtcpp cpapellggpsvfIfppkpkd tlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsItclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwgggnvfsc svmhealhnhytg kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf 1fppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakg qprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 744. CD70_ll_CCx CD3-scFc VH CDR1 Syams 745. CD70_ll_CCx CD3-scFc VH CDR2 aisgsggrtfyaesveg 746. CD70_ll_CCx CD3-scFc VH CDR3 hdysnypyfdy 747. CD70_ll_CCx CD3-scFc VL CDR1 rasqsvrsnyla

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748. CD70_ll_CCx CD3-scFc VL CDR2 gassrat 749. CD70_ll_CCx CD3-scFc VL CDR3 qqygdlpft 750. CD70_ll_CCx CD3-scFc VH evqllesgggmvqpgqslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 751. CD70_ll_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsvr snylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgcgtkveik 752. CD70_ll_CCx CD3-scFc scFv evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eik 753. CD70_ll_CCx CD3-scFc bispecific molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts

- 308 043309

gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 754. CD70_ll_CCx CD3-scFc bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfifppkpk dtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgn vfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiska kgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn

- 309 043309

vfscsvmhealhnhytqkslslspgk 755. CD70_llxCD3 -scFc VH evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 756. CD70_llxCD3 -scFc VL eivltqspgtlslspgeratlscrasqsvr snylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgpgtkveik 757. CD70_llxCD3 -scFc scFv evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eik 758. CD70_llxCD3 -scFc bispecific molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl

- 310 043309

759. CD70_llxCD3 -scFc bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprqliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlqgggdkthtcpp cpapellggpsvfIfppk pkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytIppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwq qgnvfscsvmhealhnhytq kslslspqKggggsggggsggggsggggsg gggsgggqsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap i ektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 760. CD70_12_CCx CD3-scFc VH CDR1 Syams

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761. CD70_12_CCx CD3-scFc VH CDR2 aisgsggrtfyaesveg 762. CD70_12_CCx CD3-scFc VH CDR3 hdysnypyfdy 763. CD70_12_CCx CD3-scFc VL CDR1 rasqsvrssyla 764. CD70_12_CCx CD3-scFc VL CDR2 gassrat 765. CD70_12_CCx CD3-scFc VL CDR3 qqygsspft 766. CD70_12_CCx CD3-scFc VH evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 767. CD70_12_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygsspftfgcgtkveik 768. CD70_12_CCx CD3-scFc scFv evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratiserasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkv eik 769. CD70_12_CCx CD3-scFc bispecific molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkv

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eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnyp nwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 770. CD70_12_CCx CD3-scFc bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtl misrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utIppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscs vmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthteppepapellggpsvf

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1fppkpkdtImisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvd ksrwqqgn vfscsvmhealhnhytqkslslspgk 771. CD70_12xCD3 -scFc VH evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 772. CD70_12xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygsspftfgpgtkveik 773. CD70_12xCD3 -scFc scFv evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkv eik 774. CD70_12xCD3 -scFc bispecifically ical molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta

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Ylqmnnlktedtavycvrhgnfgnsyisu WaywgqgtvtvtvtvtvtvtvtsggggggggggggggggggggggggggggggggggggggggggggggggggggggggggggGSPSLTVTVTCGAVTS GNYPNWVKPGPRGGGGTKGTP ARFS GSLLGGKAALTLSGVQPEEYYCV IWYSNRWVFGGGGTKLTVL 775. CD70_12xCD3 -scFc bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisу wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlqgggdkthtcpp cpape11ggpsvfIfppkpk dtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgn vfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpape11ggpsvf IfppkpkdtImisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap

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iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 776. CD70_13_CCx CD3-scFc VH CDR1 Syams 777. CD70_13_CCx CD3-scFc VH CDR2 aisgsggstfyaesvqg 778. CD70_13_CCx CD3-scFc VH CDR3 hdysnypyfdy 779. CD70_13_CCx CD3-scFc VL CDR1 rasqsvrgnyla 780. CD70_13_CCx CD3-scFc VL CDR2 gassrat 781. CD70_13_CCx CD3-scFc VL CDR3 qqygyspft 782. CD70_13_CCx CD3-scFc VH evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggstfу aesvqgrftisrdnskntlylqvnslraed tavyycarhdysnypyfdywgqgtlvtvss 783. CD70_13_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsvr gnylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygyspftfgcgtkveik 784. CD70_13_CCx CD3-scFc scFv evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggstfу aesvqgrftisrdnskntlylqvnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrgnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspftfgcgtkv eik 785. CD70_13_CCx CD3-scFc bispecifically cheskaya evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggstfу

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molecule aesvqgrftisrdnskntlylqvnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrgnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspftfgcgt kv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gny pnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 786. CD70_13_CCx CD3-scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggstfу aesvqgrftisrdnskntlylqvnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrgnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdt lmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke

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ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggps vf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdks rwqqgn vfscsvmhealhnhytqkslslspgk 787. CD70_13xCD3 -scFc VH evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggstfу aesvqgrftisrdnskntlylqvnslraed tavyycarhdysnypyfdywgqgtlvtvss 788. CD70_13xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsvr gnylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygyspftfgpgtkveik 789. CD70_13xCD3 -scFc scFv evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggstfу aesvqgrftisrdnskntlylqvnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrgnylawyqqkp gqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspftfgpgtkv eik 790. CD70_13xCD3 -scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggstfu aesvqgrftisrdnskntlylqvnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp

- 318 043309

geratlscrasqsvrgnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspftfgpgtkv eiksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 791. CD70_13xCD3 -scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggstfу aesvqgrftisrdnskntlylqvnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrgnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspftfgpgtkv eiksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkd tlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys

-319043309

kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykck vsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 792. CD70_14_CCx CD3-scFc VH CDR1 tyams 793. CD70_14_CCx CD3-scFc VH CDR2 aisgsgggtfyaesvkg 794. CD70_14_CCx CD3-scFc VH CDR3 hdysnypyfdy 795. CD70_14_CCx CD3-scFc VL CDR1 rasqsirsnyla 796. CD70_14_CCx CD3-scFc VL CDR2 gassrat 797. CD70_14_CCx CD3-scFc VL CDR3 qqygsspft 798. CD70_14_CCx CD3-scFc VH evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsgggtfu aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 799. CD70_14_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsir snylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygsspftfgcgtkveik 800. CD70_14_CCx CD3-scFc scFv evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsgggtfu aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp

- 320 043309

geratlscrasqsirsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkv eik 801. CD70_14_CCx CD3-scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs tyamswvrqapgkclewvsaisgsgggtfu aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkp gqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 802. CD70_14_CCx CD3-scFc bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs tyamswvrqapgkclewvsaisgsgggtfu aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkp gqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts

- 321 043309

gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsv ltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdktht cppcpapellggpsvf ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsd gsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 803. CD70_14xCD3 -scFc VH evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvsaisgsgggtfu aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 804. CD70_14xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsir snylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygsspftfgpgtkveik 805. CD70_14xCD3 -scFc scFv evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvsaisgsgggtfu aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkv

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eik 806. CD70_14xCD3 -scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvsaisgsgggtfu aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta uIqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 807. CD70_14xCD3 -scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvsaisgsgggtfu aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp

- 323 043309

cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv уtlppsreemtknqvsItclvkgfypsdia vewesngqpennykttppvldsdgs fflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf 1fppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwl ngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 808. CD70_15_CCx CD3-scFc VH CDR1 tyams 809. CD70_15_CCx CD3-scFc VH CDR2 lisgsggrtyyaesvkg 810. CD70_15_CCx CD3-scFc VH CDR3 hdysnypyfdy 811. CD70_15_CCx CD3-scFc VL CDR1 rasqsvrsnyla 812. CD70_15_CCx CD3-scFc VL CDR2 gasnrat 813. CD70_15_CCx CD3-scFc VL CDR3 qqygisppt 814. CD70_15_CCx CD3-scFc VH evqllesggglvqpggslrIscaasgftfs tyamswvrqapgkclewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 815. CD70_15_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsvr snylawyqqkpgqaprlliygasnratgip drfsgsgsgtdftltisrlepedfavyscq

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qygispptfgcgtkveik 816. CD70_15_CCx CD3-scFc scFv evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkclewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygasnratgipdrfsgsgsgtdftit isrlepedfavyscqqygispptfgcgtkv eik 817. CD70_15_CCx CD3-scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkclewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygasnratgipdrfsgsgsgtdftit isrlepedfavyscqqygispptfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 818. CD70_15_CCx CD3-scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkclewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygasnratgipdrfsgsgsgtdftit isrlepedfavyscqqygispptfgcgtkv

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eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnyp nwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlh qdwlngke ykckvsnkalpapiektiskakgqprepqv ytIppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthteppepapell ggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitv dksrwqqgn vfscsvmhealhnhytqkslslspgk 819. CD70_15xCD3 -scFc VH evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 820. CD70_15xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsvr snylawyqqkpgqaprlliygasnratgip drfsgsgsgtdftltisrlepedfavyscq qygispptfgggtkveik 821. CD70_15xCD3 -scFc scFv evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvslisgsggrtyy

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aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgqap rlliygasnratgipdrfsgsgsgtdftit isrlepedfavyscqqygispptfgggtkv e ik 822. CD70_15xCD3 -scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs tyamswvrqapgkglewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpg qap rlliygasnratgipdrfsgsgsgtdftit isrlepedfavyscqqygispptfgggtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprqliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 823. CD70_15xCD3 -scFc bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs tyamswvrqapgkglewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpg qap rlliygasnratgipdrfsgsgsgtdftit isrlepedfavyscqqygispptfgggtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta

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ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl ggggdkthtcpp cpape11ggpsvfIfppkpkdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpenny kttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpape11ggpsvf IfppkpkdtImisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvs vltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmheaIhnhytqkslslspgk 824. CD70_16_CCx CD3-scFc VH CDR1 Syams 825. CD70_16_CCx CD3-scFc VH CDR2 aisgsggraqyaesvqg 826. CD70_16_CCx CD3-scFc VH CDR3 hdysnypyfdy 827. CD70_16_CCx CD3-scFc VL CDR1 rasqsvssnla 828. CD70_16_CCx CD3-scFc VL CDR2 gsssrat 829. CD70_16_CCx CD3-scFc VL CDR3 qqygssppp 830. CD70_16_CCx VH evqllesggglvqpggslrIscaasgftfs

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CD3-scFc syamswvrqspgkclewvsaisgsggraqy aesvqgrftvsrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 831. CD70_16_CCx CD3-scFc VL eivltqspatlsvspgeratlscrasqsvs snlawyqqkpgqaprlliygsssratgipd rfsgsgsgtdftltisrlepedfavyycqq ygsspppfgcgtkveik 832. CD70_16_CCx CD3-scFc scFv evqllesggglvqpggslrIscaasgftfs syamswvrqspgkclewvsaisgsggraqy aesvqgrftvsrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspatlsvsp geratlscrasqsvssnlawyqqkp gqapr lliygsssratgipdrfsgsgsgtdftlti srlepedfavyycqqygsspppfgcgtkve ik 833. CD70_16_CCx CD3-scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs syamswvrqspgkclewvsaisgsggraqy aesvqgrftvsrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspatlsvsp geratlscrasqsvssnlawyqqkp gqapr lliygsssratgipdrfsgsgsgtdftlti srlepedfavyycqqygsspppfgcgtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgnsyis yw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvl 834. CD70_16_CCx CD3-scFc bispecifically cheskaya evqllesggglvqpggslrIscaasgftfs syamswvrqspgkclewvsaisgsggraqy

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HLE molecule aesvqgrftvsrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspatlsvsp geratlscrasqsvssnlawyqqkpgqapr lliygsssratgipdrfsgsgsgtdftiti srlepedfavyycqqygsspppfgcg tkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavt sg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvlggggdkthtcppc papellggpsvf1fppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvs vltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgfypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspgKggggsggggsggggsggggsgg ggsggggsdkthtcppcp apellggpsvf1 fppkpkdtlmisrtpevtcvvvdvshedpe vkfnwyvdgvevhnaktkpceeqygstyrc vsvltvlhqdwlngkeykckvsnkalpapi ektiskakgqprepqvytlppsreemtknq vsltclvkgfypsdiavewesngqpennyk ttppvldsdgsfflyskitvdks rwqqgnv fscsvmhealhnhytqkslslspgk 835. CD70_16xCD3 -scFc VH evqllesggglvqpggslrlscaasgftfs syamswvrqspgkglewvsaisgsggraqy aesvqgrftvsrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss

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836. CD70_16xCD3 -scFc VL eivltqspatlsvspgeratlscrasqsvs snlawyqqkpgqaprlliygsssratgipd rfsgsgsgtdftltisrlepedfavyycqq ygsspppfgggtkveik 837. CD70_16xCD3 -scFc scFv evqllesggglvqpggslrlscaasgftfs syamswvrqspgkglewvsaisgsggraqy aesvqgrftvsrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspatlsvsp geratlscrasqsvssnlawyqqkpg qapr lliygsssratgipdrfsgsgsgtdftlti srlepedfavyycqqygsspppfgggtkve ik 838. CD70_16xCD3 -scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs syamswvrqspgkglewvsaisgsggraqy aesvqgrftvsrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspatlsvsp geratlscrasqsvssnlawyqqkpg qapr lliygsssratgipdrfsgsgsgtdftlti srlepedfavyycqqygsspppfgggtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay 1qmnnlktedtavyycvrhgnfgnsyisy w aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvl 839. CD70_16xCD3 -scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqspgkglewvsaisgsggraqy aesvqgrftvsrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspatlsvsp

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geratlscrasqsvssnlawyqqkpgqapr lliygsssratgipdrfsgsgsgtdftlti srlepedfavyycqqygsspppfgggtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay iqmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvl ggggdkthtcppc papellggpsvfifppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgfypsdiav ewesnggpennykttppv ldsdgsfflysk 1tvdksrwqqgnvfscsvmhealhnhytqk slslspgKggggsggggsggggsggggsgg ggsggggsdkthtcppcpapellggpsvf1 fppkpkdtlmisrtpevtcvvvdvshedpe vkfnwyvdgvevhnaktkpceeqygstyrc vsvltvlhqd wlngkeykckvsnkalpapi ektiskakgqprepqvytlppsreemtknq vsltclvkgfypsdiavewesngqpennyk ttppvldsdgsfflyskitvdksrwqqgnv fscsvmhealhnhytqkslslspgk 840. CD70_17_CCx CD3-scFc VH CDR1 Syams 841. CD70_17_CCx CD3-scFc VH CDR2 aisgsggrtfyaesveg 842. CD70_17_CCx CD3-scFc VH CDR3 hdysnypyfdy 843. CD70_17_CCx VL CDR1 rasqgvrsdyla

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CD3-scFc 844. CD70_17_CCx CD3-scFc VL CDR2 gassrat 845. CD70_17_CCx CD3-scFc VL CDR3 ggygstppt 846. CD70_17_CCx CD3-scFc VH evgllesgggmvgpggslrlscaasgftfs syamswvrgapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylgmnslraed tavyyctkhdysnypyfdywgggtlvtvss 847. CD70_17_CCx CD3-scFc VL eivltgspgtlslspgeratlscrasqgvr sdylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyhcq gygstpptfgcgtkveik 848. CD70_17_CCx CD3-scFc scFv evgllesgggmvgpggslrlscaasgftfs syamswvrgapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylgmnslraed tavyyctkhdysnypyfdywgggtlvtvss ggggsggggsggggseivltgspgtlslsp geratlscrasqgvrsdylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyhcqqygstpptfgcgtkv eik 849. CD70_17_CCx CD3-scFc bispecific molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrsdylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyhcgqygstpptfgcgtkv eiksggggsevglvesggglvgpggslkls caasgftfnkyamnwvrgapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylgmnnlktedtavyycvrhgnfgnsyisy wayw gggtlvtvssggggsggggsggggsg

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tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 850. CD70_17_CCx CD3-scFc bispecific HLE molecule evqllesgggmvqpgqslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrsdylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyhcqqygstpptfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkd tImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnv fscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf 1fppkpkdtImisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektis kakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny

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kttppvldsdgsfflyskitvdksrwqqgn vfscsvmheaIhnhytqkslslspgk 851. CD70_17xCD3 -scFc VH evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss 852. CD70_17xCD3 -scFc VL eivltqspgtlslspgeratlscrasqgvr sdylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyhcq qygstpptfgggtkveik 853. CD70_17xCD3 -scFc scFv evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrsdylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyhcqqygstpptfgggtkv eik 854. CD70_17xCD3 -scFc bispecific molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrsdylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyhcqqygstpptfgggtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprqliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv

- 335 043309

Iwysnrwvfgggtkltvl 855. CD70_17xCD3 -scFc bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrsdylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyhcqqygstpptfgggtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdtl misrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscs vmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapelIggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprep qvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 856. CD70_18_CCx VH CDR1 Syams

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CD3-scFc 857. CD70_18_CCx CD3-scFc VH CDR2 aigeggytyyaesvkg 858. CD70_18_CCx CD3-scFc VH CDR3 hdysnypyfdy 859. CD70_18_CCx CD3-scFc VL CDR1 rasqgvrssyfa 860. CD70_18_CCx CD3-scFc VL CDR2 gastrate 861. CD70_18_CCx CD3-scFc VL CDR3 qqygssppt 862. CD70_18_CCx CD3-scFc VH evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaigegggytyy aesvkgrftisrdnskntlsllmnslraed tavyycarhdysnypyfdywgqgtlvtvs 863. CD70_18_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqgvr ssyfawyqqkpgqaprlliygastratgip arfsgsgsgtdftltisrlepedfavyуcq qygsspptfgcgtkveik 864. CD70_18_CCx CD3-scFc scFv evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaigegggytyy aesvkgrftisrdnskntlsllmnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssyfawyqqkpgqap r lliygastratgiparfsgsgsgtdftit isrlepedfavyycqqygsspptfgcgtkv eik 865. CD70_18_CCx CD3-scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaigegggytyy aesvkgrftisrdnskntlsllmnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssyfawyqqkpgqap r lliygastratgiparfsgsgsgtdftit

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isrlepedfavyycqqygsspptfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvt qepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 866. CD70_18_CCx CD3-scFc bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvsaigegggytyy aesvkgrftisrdnskntlsllmnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssyfawyqqkpgqap rlliygastratgiparfsgsgsgtdftit isrlepedfavyycqqygsspptfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtv ssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtc vvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhn hytq kslslspgKggggsgqggsggggsggggsg

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gggsggggsdkthteppepapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqp enny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 867. CD70_18xCD3 -scFc VH evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaigegggytyy aesvkgrftisrdnskntlsllmnslraed tavyycarhdysnypyfdywgqgtlvtvss 868. CD70_18xCD3 -scFc VL eivltqspgtlslspgeratlscrasqgvr ssyfawyqqkpgqaprlliygastratgip arfsgsgsgtdftltisrlepedfavyycq qygsspptfgqgtkveik 869. CD70_18xCD3 -scFc scFv evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaigegggytyy aesvkgrftisrdnskntlsllmnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssyfawyqqkpgqap r lliygastratgiparfsgsgsgtdftit isrlepedfavyycqqygsspptfgqgtkv eik 870. CD70_18xCD3 -scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaigegggytyy aesvkgrftisrdnskntlsllmnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssyfawyqqkpgqap r lliygastratgiparfsgsgsgtdftit isrlepedfavyycqqygsspptfgqgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari

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rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaey ycv Iwysnrwvfgggtkltvl 871. CD70_18xCD3 -scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaigegggytyy aesvkgrftisrdnskntlsllmnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssyfawyqqkpgqap r lliygastratgiparfsgsgsgtdftit isrlepedfavyycqqygsspptfgqgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvs sggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdtlmisrtpe vtcv vvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhyt q kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapelIggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr

- 340 043309

cvsvltvlhqdwlngkeykckvsnkalpap 1ektiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 872. CD70_19_CCx CD3-scFc VH CDR1 Syams 873. CD70_19_CCx CD3-scFc VH CDR2 aisgsggrtfyaesveg 874. CD70_19_CCx CD3-scFc VH CDR3 hdysnypyfdy 875. CD70_19_CCx CD3-scFc VL CDR1 rasqsirsnyla 876. CD70_19_CCx CD3-scFc VL CDR2 gassrat 877. CD70_19_CCx CD3-scFc VL CDR3 qqygsspps 878. CD70_19_CCx CD3-scFc VH evqllesgggvvqpgrsirIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 879. CD70_19_CCx CD3-scFc VL eivltqspgtlslspqeratlscrasqsir snylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygssppsfgcgtkveik 880. CD70_19_CCx CD3-scFc scFv evqllesgggvvqpgrsirIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygssppsfgcgtkv elk 881. CD70_19_CCx bispecifically evqllesgggvvqpgrsirIscaasgftfs

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CD3-scFc cheskaya molecule syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdft it isrlepedfavyycqqygssppsfgcgtkv eiksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tv vtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 882. CD70_19_CCx CD3-scFc bispecific HLE molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygssppsfgcgtkv eiksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkd tlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak

-342043309

tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggs ggggsg gggsggggsdkthtcppcpapellggpsvf 1fppkpkdtImisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfyps diavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 883. CD70_19xCD3 -scFc VH evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 884. CD70_19xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsir snylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygssppsfgqgtkveik 885. CD70_19xCD3 -scFc scFv evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygssppsfgqgtkv eik 886. CD70_19xCD3 -scFc bispecific molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss

- 343 043309

ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygssppsfgqgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rsky nnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 887. CD70_19xCD3 -scFc bispecific HLE molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygssppsfgqgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdt lmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia

-344043309

vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpcee qygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 888. CD70_20_CCx CD3-scFc VH CDR1 Syams 889. CD70_20_CCx CD3-scFc VH CDR2 aisgsgggtfyaesveg 890. CD70_20_CCx CD3-scFc VH CDR3 hdysnypyfdy 891. CD70_20_CCx CD3-scFc VL CDR1 rasqsvrssyla 892. CD70_20_CCx CD3-scFc VL CDR2 gassrat 893. CD70_20_CCx CD3-scFc VL CDR3 qqygdlpft 894. CD70_20_CCx CD3-scFc VH evqllesgggvvqpgrslrIscaasgftfs syamswvrqapgkclewvsaisgsgggtfu aesvegrftisrdnskntlylqmnslraed tavyycarhdysnypyfdywglgtlvtvss 895. CD70_20_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyscq qygdlpftfgcgtkveik 896. CD70_20_CCx CD3-scFc scFv evqllesgggvvqpgrslrIscaasgftfs syamswvrqapgkclewvsaisgsgggtfu aesvegrftisrdnskntlylqmnslraed tavyycarhdysnypyfdywglgtlvtvss

- 345 043309

ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgcgtkv elk 897. CD70_20_CCx CD3-scFc bispecific molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkclewvsaisgsgggtfu aesvegrftisrdnskntlylqmnslraed tavyycarhdysnypyfdywglgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 898. CD70_20_CCx CD3-scFc bispecific HLE molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkclewvsaisgsgggtfu aesvegrftisrdnskntlylqmnslraed tavyycarhdysnypyfdywglgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq

- 346 043309

tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkpkdtImisrtpe vtcvvvdvshedpevkf nwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgK ggggsggggsggggsggggsg gggsggggsdkthtcppcpape11ggpsvf IfppkpkdtImisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qv sltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 899. CD70_20xCD3 -scFc VH evqllesgggvvqpgrsirIscaasgftfs syamswvrqapgkglewvsaisgsgggtfu aesvegrftisrdnskntlylqmnslraed tavyycarhdysnypyfdywglgtlvtvss 900. CD70_20xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyscq qygdlpftfgpgtkveik 901. CD70_20xCD3 -scFc scFv evqllesgggvvqpgrsirIscaasgftfs syamswvrqapgkglewvsaisgsgggtfu aesvegrftisrdnskntlylqmnslraed tavyycarhdysnypyfdywglgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit

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isrlepedfavyscqqygdlpftfgpgtkv eik 902. CD70_20xCD3 -scFc bispecific molecule evqllesgggvvqpgrsirIscaasgftfs syamswvrqapgkglewvsaisgsgggtfu aesvegrftisrdnskntlylqmnslraed tavyycarhdysnypyfdywglgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 903. CD70_20xCD3 -scFc bispecific HLE molecule evqllesgggvvqpgrsirIscaasgftfs syamswvrqapgkglewvsaisgsgggtfu aesvegrftisrdnskntlylqmnslraed tavyycarhdysnypyfdywglgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv

- 348 043309

Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvs ltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvev hnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 904. CD70_21_CCx CD3-scFc VH CDR1 Syams 905. CD70_21_CCx CD3-scFc VH CDR2 aisgsggrtfyaesveg 906. CD70_21_CCx CD3-scFc VH CDR3 hdysnypyfdy 907. CD70_21_CCx CD3-scFc VL CDR1 rasqsvrssyla 908. CD70_21_CCx CD3-scFc VL CDR2 gassrat 909. CD70_21_CCx CD3-scFc VL CDR3 qqygdlpft 910. CD70_21_CCx CD3-scFc VH evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss 911. CD70_21_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip

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drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgcgtkvdik 912. CD70_21_CCx CD3-scFc scFv evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv dik 913. CD70_21_CCx CD3-scFc bispecifically ical molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 914. CD70_21_CCx CD3-scFc bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit

- 350 043309

isrlepedfavyycqqygdlpftfgcgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvv tqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfifppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvd gvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggs ggggsggggsg gggsggggsdkthtcppcpapellggpsvf ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfy psdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 915. CD70_21xCD3 -scFc VH EvqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss 916. CD70_21xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgpgtkvdik 917. CD70_21xCD3 scFv EvqllesgggmvqpggslrIscaasgftfs

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-scFc syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdft it isrlepedfavyycqqygdlpftfgpgtkv dik 918. CD70_21xCD3 -scFc bispecifically ical molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 919. CD70_21xCD3 -scFc bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari

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rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaey ycv Iwysnrwvfgggtkitvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqv sItclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf 1fppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvd gvevhnaktkpceegygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 920. CD70_22_CCx CD3-scFc VH CDR1 tyams 921. CD70_22_CCx CD3-scFc VH CDR2 lisgsggrtyyaesvkg 922. CD70_22_CCx CD3-scFc VH CDR3 hdysnypyfdy 923. CD70_22_CCx CD3-scFc VL CDR1 rasqgvrssyla 924. CD70_22_CCx CD3-scFc VL CDR2 gassrat 925. CD70_22_CCx CD3-scFc VL CDR3 qqygssppt

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926. CD70_22_CCx CD3-scFc VH evqllesggglvqpggslrIscaasgftfs tyamswvrqapgkclewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 927. CD70_22_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqgvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftitinriepedfavyycq qygsspptfgcgtkvdik 928. CD70_22_CCx CD3-scFc scFv evqllesggglvqpggslrIscaasgftfs tyamswvrqapgkclewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgcgtkv dik 929. CD70_22_CCx CD3-scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs tyamswvrqapgkclewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgcgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprqliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 930. CD70_22_CCx bispecifically evqllesggglvqpggslrIscaasgftfs

- 354 043309

CD3-scFc cheskaya HLE molecule tyamswvrqapgkclewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtd ftit inrlepedfavyycqqygsspptfgcgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvt qepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdg vevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsgg ggsggggsg gggsggggsdkthtcppcpapelIggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvs1tclvkgfy psdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 931. CD70_22xCD3 -scFc VH evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed

- 355 043309

tavyycakhdysnypyfdywgqgtlvtvss 932. CD70_22xCD3 -scFc VL eivltqspgtlslspgeratlscrasqgvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltinrlepedfavyycq qygsspptfgggtkvdik 933. CD70_22xCD3 -scFc scFv evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgggtkv dik 934. CD70_22xCD3 -scFc bispecifically ical molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgggtkv diksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 935. CD70_22xCD3 -scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss

- 356 043309

ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgggtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyaty yadsvkdrftisrddsknta uIqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwy snrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv уtlppsreemtknqvsltclvkgf ypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkp ceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 936. CD70_23_CCx CD3-scFc VH CDR1 Syams 937. CD70_23_CCx CD3-scFc VH CDR2 aisgsggrtfyaesveg 938. CD70_23_CCx CD3-scFc VH CDR3 hdysnypyfdy

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939. CD70_23_CCx CD3-scFc VL CDR1 rasqsvrsnyla 940. CD70_23_CCx CD3-scFc VL CDR2 gassrat 941. CD70_23_CCx CD3-scFc VL CDR3 qqygssppt 942. CD70_23_CCx CD3-scFc VH evgllesgggvvgpgrslrlscaasgftfs syamswvrgapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylgmnslraed tavyycakhdysnypyfdywgggtlvtvss 943. CD70_23_CCx CD3-scFc VL eivltgspgtlslspgeratlscrasqsvr snylawyggkpggaprlliygassratgip drfsgsgsgtdftltinrlepedfavyycg gygsspptfgcgtkvdik 944. CD70_23_CCx CD3-scFc scFv evgllesgggvvgpgrslrlscaasgftfs syamswvrgapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylgmnslraed tavyycakhdysnypyfdywgggtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasgsvrsnylawyggkpggap rlli ygassratgipdrfsgsgsgtdftit inrlepedfavyycgqygsspptfgcgtkv dik 945. CD70_23_CCx CD3-scFc bispecific molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrgapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylgmnslraed tavyycakhdysnypyfdywgggtlvtvss ggggsggggsggggseivltgspgtlslsp geratlscrasgsvrsnylawyggkpggap rlli ygassratgipdrfsgsgsgtdftit inrlepedfavyycgqygsspptfgcgtkv diksggggsevglvesggglvgpggslkls caasgftfnkyamnwvrgapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylgmnnlktedtavyycvrhgnfgnsyisy

- 358 043309

waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 946. CD70_23_CCx CD3-scFc bispecific HLE molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgcgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmis rtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscs vmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprep qvytlppsreemtkn

- 359 043309

qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 947. CD70_23xCD3 -scFc VH evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 948. CD70_23xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsvr snylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltinrlepedfavyycq qygsspptfgggtkvdik 949. CD70_23xCD3 -scFc scFv evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgggtkv dik 950. CD70_23xCD3 -scFc bispecific molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgggtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqg tlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp

- 360 043309

arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 951. CD70_23xCD3 -scFc bispecific HLE molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgggtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqg tlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrt pe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvm healhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvy tlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk

- 361 043309

952. CD70_24_CCx CD3-scFc VH CDR1 Syams 953. CD70_24_CCx CD3-scFc VH CDR2 visgsggitdfaesvkg 954. CD70_24_CCx CD3-scFc VH CDR3 hdysnyfffdy 955. CD70_24_CCx CD3-scFc VL CDR1 rasqgisnyla 956. CD70_24_CCx CD3-scFc VL CDR2 aasilqs 957. CD70_24_CCx CD3-scFc VL CDR3 qqyfaypit 958. CD70_24_CCx CD3-scFc VH evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsvisgsggitdf aesvkgrftisrdnsrntlylqmnslraed tavyfcarhdysnyfffdywgqgtlvtvss 959. CD70_24_CCx CD3-scFc VL diqmtqspsslsasvgdrvtitcrasqgis nylawyqqkpgkvpklliyaasilqsgvps kfsgsgsgtdftltisslqpedfaiyycqq yfaypitfgcgtrleik 960. CD70_24_CCx CD3-scFc scFv evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsvisgsggitdf aesvkgrftisrdnsrntlylqmnslraed tavyfcarhdysnyfffdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyqqkp gkvpk lliyaasilqsgvpskfsgsgsgtdftlti sslqpedfaiyycqqyfaypitfgcgtrle ik 961. CD70_24_CCx CD3-scFc bispecific molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsvisgsggitdf aesvkgrftisrdnsrntlylqmnslraed tavyfcarhdysnyfffdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyqqkp gkvpk

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lliyaasilqsgvpskfsgsgsgtdftlti sslqpedfaiyycqqyfaypitfgcgtrle iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgnsyisyw a ywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvl 962. CD70_24_CCx CD3-scFc bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvsvisgsggitdf aesvkgrftisrdnsrntlylqmnslraed tavyfcarhdysnyfffdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyqqk pgkvpk lliyaasilqsgvpskfsgsgsgtdftlti sslqpedfaiyycqqyfaypitfgcgtrle iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgn syisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvlggggdkthtcppc pape11ggpsv fIfppkpkdtImisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgfypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqq gnvfscsvmhealhnhytqk

- 363 043309

slslspgKggggsggggsggggsggggsgg ggsggggsdkthtcppcpapellggpsvf1 fppkpkdtImisrtpevtcvvvdvshedpe vkfnwyvdgvevhnaktkpceeqygstyrc vsvltvlhqdwlngkeykckvsnkalpapi ektiskakgqprepqvytlppsreemtk nq vsltclvkgfypsdiavewesngqpennyk ttppvldsdgsfflyskitvdksrwqqgnv fscsvmhealhnhytqkslslspgk 963. CD70_24xCD3 -scFc VH evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsvisgsggitdf aesvkgrftisrdnsrntlylqmnslraed tavyfcarhdysnyfffdywgqgtlvtvss 964. CD70_24xCD3 -scFc VL diqmtqspsslsasvgdrvtitcrasqgis nylawyqqkpgkvpklliyaasilqsgvps kfsgsgsgtdftltisslqpedfaiyycqq yfaypitfgqgtrleik 965. CD70_24xCD3 -scFc scFv evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsvisgsggitdf aesvkgrftisrdnsrntlylqmnslraed tavyfcarhdysnyfffdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyqqk pgkvpk lliyaasilqsgvpskfsgsgsgtdftlti sslqpedfaiyycqqyfaypitfgqgtrle ik 966. CD70_24xCD3 -scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsvisgsggitdf aesvkgrftisrdnsrntlylqmnslraed tavyfcarhdysnyfffdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyqqk pgkvpk lliyaasilqsgvpskfsgsgsgtdftlti sslqpedfaiyycqqyfaypitfgqgtrle iksggggsevqlvesggglvqpggslklsc

- 364 043309

aasgftfnkyamnwvrqapgkglewvarig skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkfla pgtpa rfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvl 967. CD70_24xCD3 -scFc bispecific HLE molecule evqllesggglvqpggslriscaasgftfs syamswvrqapgkglewvsvisgsggitdf aesvkgrftisrdnsrntlylqmnslraed tavyfcarhdysnyfffdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyqqkpg kvpk lliyaasilqsgvpskfsgsgsgtdftlti sslqpedfaiyycqqyfaypitfgqgtrle iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgnsyis yw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfifpp kpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgfypsdiav ewesngqpennykttppvldsdgsfflysk itvdksrwqqgnvf scsvmhealhnhytqk slslspgKggggsggggsggggsggggsgg ggsggggsdkthtcppcpapellggpsvf1 fppkpkdtlmisrtpevtcvvvdvshedpe

- 365 043309

vkfnwyvdgvevhnaktkpceeqygstyrc vsvltvlhqdwlngkeykckvsnkalpapi ektiskakgqprepqvytlppsreemtknq vsItclvkgfypsdiavewesngqpennyk ttppvldsdgsfflyskitvdksrwqqgnv fscsvmhealhnhytqkslslspgk 968. CD70_25_CCx CD3-scFc VH CDR1 Syams 969. CD70_25_CCx CD3-scFc VH CDR2 aisgsggrtfyaesveg 970. CD70_25_CCx CD3-scFc VH CDR3 hdysnypyfdy 971. CD70_25_CCx CD3-scFc VL CDR1 rasqsvrssyla 972. CD70_25_CCx CD3-scFc VL CDR2 gassrat 973. CD70_25_CCx CD3-scFc VL CDR3 qqygssppt 974. CD70_25_CCx CD3-scFc VH evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 975. CD70_25_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyfcq qygsspptfgcgtrleik 976. CD70_25_CCx CD3-scFc scFv evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgcgtrl elk

- 366 043309

977. CD70_25_CCx CD3-scFc bispecific molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgcgtrl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 978. CD70_25_CCx CD3-scFc bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgcgtrl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdtlmis rtpe

-367 043309

vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utIppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvm healhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvy tlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 979. CD70_25xCD3 -scFc VH evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 980. CD70_25xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyfcq qygsspptfgggtrleik 981. CD70_25xCD3 -scFc scFv evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgggtrl eik 982. CD70_25xCD3 -scFc bispecific molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed

- 368 043309

tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgggtrl eiksqgggsevqlvesggglvqpggslkls caas qftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 983. CD70_25xCD3 -scFc bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgggtrl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmis rtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv

-369 043309

ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvd vshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslsl spgk 984. CD70_26_CCx CD3-scFc VH CDR1 iyams 985. CD70_26_CCx CD3-scFc VH CDR2 aiggsggstfyaesvkg 986. CD70_26_CCx CD3-scFc VH CDR3 hdysnypyfdy 987. CD70_26_CCx CD3-scFc VL CDR1 rasqsvrssyva 988. CD70_26_CCx CD3-scFc VL CDR2 gassrat 989. CD70_26_CCx CD3-scFc VL CDR3 qqygdlpft 990. CD70_26_CCx CD3-scFc VH evqllesggglvqpggslrlscaasgftfs iyamswvrqapgkclewvsaiggsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 991. CD70_26_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsvr ssyvawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgcgtrleik 992. CD70_26_CCx CD3-scFc scFv evqllesggglvqpggslrlscaasgftfs iyamswvrqapgkclewvsaiggsggstfу aesvkgrftisrdnskntlylqmnslraed

- 370 043309

tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssyvawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtrl elk 993. CD70_26_CCx CD3-scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs iyamswvrqapgkclewvsaiggsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssyvawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtrl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkitvl 994. CD70_26_CCx CD3-scFc bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs iyamswvrqapgkclewvsaiggsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssyvawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtrl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy

- 371 043309

waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkp kdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgn vfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiska kgqprepqvytlppsreemtkn qvs1tclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 995. CD70_26xCD3 -scFc VH evqllesggglvqpggslrlscaasgftfs iyamswvrqapgkglewvsaiggsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss 996. CD70_26xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsvr ssyvawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgpgtrleik 997. CD70_26xCD3 -scFc scFv evqllesggglvqpggslrlscaasgftfs iyamswvrqapgkglewvsaiggsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssyvawyqqkpgq ap

- 372 043309

rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtg1 eik 998. CD70_26xCD3 -scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs iyamswvrqapgkglewvsaiggsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssyvawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtrl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 999. CD70_26xCD3 -scFc bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs iyamswvrqapgkglewvsaiggsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssyvawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtrl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp

- 373 043309

arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiska kgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevt cvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhy tqkslslspgk 1000. CD70_27_CCx CD3-scFc VH CDR1 sssyywg 1001. CD70_27_CCx CD3-scFc VH CDR2 siyhsggtyfnpslks 1002. CD70_27_CCx CD3-scFc VH CDR3 hyeiltgyypdvfdi 1003. CD70_27_CCx CD3-scFc VL CDR1 rasqsissyln 1004. CD70_27_CCx CD3-scFc VL CDR2 aasnlqs 1005. CD70_27_CCx CD3-scFc VL CDR3 qqsfssprt 1006. CD70_27_CCx CD3-scFc VH qvqlqesgpglvkpsqtlsltctvsggsis sssyywgwirqppgkclewigsiyhsggty fnpslksrvtisvdtsknqfslklssvtaa dtavyycarhyeiltgyypdvfdiwgqgtm vtvss

- 374 043309

1007. CD70_27_CCx CD3-scFc VL diqmtqspsslsasvgdrvtitcrasqsis sylnwyqqkpgkapklliyaasnlqsgvss rfsgsgsgtdftltisslqpedfatyycqq sfssprtfgcgtkveik 1008. CD70_27_CCx CD3-scFc scFv qvqlqesgpglvkpsqtlsltctvsggsis sssyywgwirqppgkclewigsiyhsggty fnpslksrvtisvdtsknqfslklssvtaa dtavyycarhyeiltgyypdvfdiwgqgtm vtvssggggsggggsggggsdiqmtqspss Isasvgdrvtitcrasqsis sylnwyqqkp gkapklliyaasnlqsgvssrfsgsgsgtd ftltisslqpedfatyycqqsfssprtfgc gtkveik 1009. CD70_27_CCx CD3-scFc bispecific molecule qvqlqesgpglvkpsqtlsltctvsggsis sssyywgwirqppgkclewigsiyhsggty fnpslksrvtisvdtsknqfslklssvtaa dtavyycarhyeiltgyypdvfdiwgqgtm vtvssggggsggggsggggsdiqmtqspss Isasvgdrvtitcrasqsis sylnwyqqkp gkapklliyaasnlqsgvssrfsgsgsgtd ftltisslqpedfatyycqqsfssprtfgc gtkveiksggggsevqlvesggglvqpggs Iklscaasgftfnkyamnwvrqapgkglew varirskynnyatyyadsvkdrftisrdds kntaylqmnnlktedta vyycvrhgnfgns yisywaywgqgtlvtvssggggsggggsgg ggsqtvvtqepsltvspggtvtltcgsstg avtsgnypnwvqqkpgqaprgliggtkf!a pgtparfsgsllggkaaltlsgvqpedeae yycvlwysnrwvfgggtkltvl 1010. CD70_27_CCx CD3-scFc bispecific HLE molecule qvqlqesgpglvkpsqtlsltctvsggsis sssyywgwirqppgkclewigsiyhsggty fnpslksrvtisvdtsknqfslklssvtaa dtavyycarhyeiltgyypdvfdiwgqgtm vtvssggggsggggsggggsdiqmtqspss

- 375 043309

Isasvgdrvtitcrasqsissylnwyqqkp gkapklliyaasnlqsgvssrfsgsgsgtd ftltisslqpedfatyycqqsfssprtfgc gtkveiksggggsevqlvesggglvqpggs Ikiscaasgftfnkyamnwvrqapgkglew varirskynnyatyyadsvkdr ftisrdds kntaylqmnnlktedtavyycvrhgnfgns yisywaywgqgtlvtvssggggsggggsgg ggsqtvvtqepsltvspggtvtltcgsstg avtsgnypnwvqqkpgqaprgliggtkf!a pgtparfsgsllggkaaltlsgvqpedeae yycvlwys nrwvfgggtkltvlggggdkth teppepapellggpsvfIfppkpkdtlmis rtpevtcvvvdvshedpevkfnwyvdgvev hnaktkpceeqygstyrcvsvltvlhqdwl ngkeykckvsnkalpapiektiskakgqpr epqvytIppsreemtknqvsltclvkgfy p sdiavewesngqpennykttppvldsdgsf flyskltvdksrwqqgnvfscsvmhealhn hytqkslslspgKggggsggggsggggsgg ggsggggsggggsdkthteppepapellgg psvfIfppkpkdtlmisrtpevtcvvvdvs hedpevkfnwyvdgvevhnaktkpce eqyg styrcvsvltvlhqdwlngkeykckvsnka Ipapiektiskakgqprepqvytlppsree mtknqvsltclvkgfypsdiavewesngqp ennykttppvldsdgsfflyskitvdksrw qqgnvfscsvmhealhnhytqkslslspgk 1011. CD70_27xCD3 -scFc VH qvqlqesgpglvkpsqtlsltctvsggsis sssyywgwirqppgkglewigsiyhsggty fnpslksrvtisvdtsknqfslklssvtaa dtavyycarhyeiltgyypdvfdiwgqgtm vtvss 1012. CD70_27xCD3 -scFc VL diqmtqspsslsasvgdrvtitcrasqsis sylnwyqqkpgkapklliyaasnlqsgvss

- 376 043309

rfsgsgsgtdftltisslqpedfatyycqq sfssprtfgqgtkveik 1013. CD70_27xCD3 -scFc scFv qvqlqesgpglvkpsqtlsltctvsggsis sssyywgwirqppgkglewigsiyhsggty fnpslksrvtisvdtsknqfslklssvtaa dtavyycarhyeiltgyypdvfdiwgqgtm vtvssggggsggggsggggsdiqmtqspss Isasvgdrvtitcrasqsis sylnwyqqkp gkapklliyaasnlqsgvssrfsgsgsgtd ftltisslqpedfatyycqqsfssprtfgq gtkveik 1014. CD70_27xCD3 -scFc bispecifically ical molecule qvqlqesgpglvkpsqtlsltctvsggsis sssyywgwirqppgkglewigsiyhsggty fnpslksrvtisvdtsknqfslklssvtaa dtavyycarhyeiltgyypdvfdiwgqgtm vtvssggggsggggsggggsdiqmtqspss Isasvqdrvtitcrasqsis sylnwyqqkp gkapklliyaasnlqsgvssrfsgsgsgtd ftltisslqpedfatyycqqsfssprtfgq gtkveiksggggsevqlvesggglvqpggs Iklscaasgftfnkyamnwvrqapgkglew varirskynnyatyyadsvkdrftisrdds kntaylqmnnlktedta vyycvrhgnfgns yisywaywgqgtlvtvssggggsggggsgg ggsqtvvtqepsltvspggtvtltcgsstg avtsgnypnwvqqkpgqaprgliggtkf!a pgtparfsgsllggkaaltlsgvqpedeae yycvlwysnrwvfgggtkltvl 1015. CD70_27xCD3 -scFc bispecific HLE molecule qvqlqesgpglvkpsqtlsltctvsggsis sssyywgwirqppgkglewigsiyhsggty fnpslksrvtisvdtsknqfslklssvtaa dtavyycarhyeiltgyypdvfdiwgqgtm vtvssggggsggggsggggsdiqmtqspss Isasvqdrvtitcrasqsis sylnwyqqkp gkapklliyaasnlqsgvssrfsgsgsgtd

- 377 043309

ftltisslqpedfatyycqqsfssprtfgq gtkveiksggggsevqlvesggglvqpggs 1klscaasgftfnkyamnwvrqapgkglew varirskynnyatyyadsvkdrftisrdds kntaylqmnnlktedtavyycvrhgnfgns yisywaywgqgtlvtvssggggsgggg sgg ggsqtvvtqepsltvspggtvtltcgsstg avtsgnypnwvqqkpgqaprgliggtkf!a pgtparfsgsllggkaaltlsgvqpedeae yycvlwysnrwvfgggtkltvlggggdkth tcppcpapellggpsvfifppkpkdtlmis rtpevtcvv vdvshedpevkfnwyvdgvev hnaktkpceeqygstyrcvsvltvlhqdwl ngkeykckvsnkalpapiektiskakgqpr epqvytlppsreemtknqvsltclvkgfyp sdiavewesngqpennykttppvldsdgsf flyskitvdksrwqqgnvfscsvmhealhn hyt qkslslspgKggggsggggsggggsgg ggsggggsggggsdkthtcppcpapellgg psvfifppkpkdtlmisrtpevtcvvvdvs hedpevkfnwyvdgvevhnaktkpceeqyg styrcvsvltvlhqdwlngkeykckvsnka ipapiektiskakgqprepqvytlppsre e mtknqvsltclvkgfypsdiavewesngqp ennykttppvldsdgsfflyskitvdksrw qqgnvfscsvmhealhnhytqkslslspgk 1016. CD70_28_CCx CD3-scFc VH CDR1 sysmn 1017. CD70_28_CCx CD3-scFc VH CDR2 yisssggyiyyaesvkg 1018. CD70_28_CCx CD3-scFc VH CDR3 gdysnyayfdy 1019. CD70_28_CCx CD3-scFc VL CDR1 rasqgisnyla 1020. CD70_28_CCx VL CDR2 aastlqs

- 378 043309

CD3-scFc 1021. CD70_28_CCx CD3-scFc VL CDR3 qqyystplt 1022. CD70_28_CCx CD3-scFc VH evqlvesggglvkpggslrlscaasgftfs sysmnwvrqapgkclewvsyisssggyiyy aesvkgrftisrdnaknslylqmnslraed aavyycsrgdysnyayfdywgqgtlvtvss 1023. CD70_28_CCx CD3-scFc VL Diqmtqspsslsasvgdrvtitcrasqgis nylawyqqkpgkvpklliyaastlqsgvps rfsgsgsgtdftltisslqaedvavyycqq yystpltfgcgtkveik 1024. CD70_28_CCx CD3-scFc scFv evqlvesggglvkpggslrlscaasgftfs sysmnwvrqapgkclewvsyisssggyiyy aesvkgrftisrdnaknslylqmnslraed aavyycsrgdysnyayfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyq qkpgkvpk lliyaastlqsgvpsrfsgsgsgtdftlti sslqaedvavyycqqyystpltfgcgtkve ik 1025. CD70_28_CCx CD3-scFc bispecific molecule evqlvesggglvkpggslrlscaasgftfs sysmnwvrqapgkclewvsyisssggyiyy aesvkgrftisrdnaknslylqmnslraed aavyycsrgdysnyayfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyq qkpgkvpk lliyaastlqsgvpsrfsgsgsgtdftlti sslqaedvavyycqqyystpltfgcgtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay 1qmnnlktedtavyyc vrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa

-379 043309

gfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvl 1026. CD70_28_CCx CD3-scFc bispecific HLE molecule evqlvesggglvkpggslrIscaasgftfs sysmnwvrqapgkclewvsyisssggyiyy aesvkgrftisrdnaknslylqmnslraed aavyycsrgdysnyayfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawy qqkpgkvpk lliyaastlqsgvpsrfsgsgsgtdftlti sslqaedvavyycqqyystpltfgcgtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyyc vrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvlggggdkthtcppc p ape11ggpsvfIfppkpkdtImisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgfypsdiav ewesngqpennykttppvldsdgsfflysk Itv dksrwqqgnvfscsvmhealhnhytqk slslspgKggggsggggsggggsggggsgg ggsggggsdkthtcppcpapellggpsvf1 fppkpkdtImisrtpevtcvvvdvshedpe vkfnwyvdgvevhnaktkpceeqygstyrc vsvltvlhqdwlngkeykckvsnkalpa pi ektiskakgqprepqvytlppsreemtknq vsltclvkgfypsdiavewesngqpennyk ttppvldsdgsfflyskitvdksrwqqgnv fscsvmhealhnhytqkslslspgk

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1027. CD70_28xCD3 -scFc VH evqlvesggglvkpggslrlscaasgftfs sysmnwvrqapgkglewvsyisssggyiyy aesvkgrftisrdnaknslylqmnslraed aavyycsrgdysnyayfdywgqgtlvtvss 1028. CD70_28xCD3 -scFc VL diqmtqspsslsasvgdrvtitcrasqgis nylawyqqkpgkvpklliyaastlqsgvps rfsgsgsgtdftltisslqaedvavyycqq yystpltfgggtkveik 1029. CD70_28xCD3 -scFc scFv evqlvesggglvkpggslrlscaasgftfs sysmnwvrqapgkglewvsyisssggyiyy aesvkgrftisrdnaknslylqmnslraed aavyycsrgdysnyayfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyq qkpgkvpk lliyaastlqsgvpsrfsgsgsgtdftlti sslqaedvavyycqqyystpltfgggtkve ik 1030. CD70_28xCD3 -scFc bispecific molecule evqlvesggglvkpggslrlscaasgftfs sysmnwvrqapgkglewvsyisssggyiyy aesvkgrftisrdnaknslylqmnslraed aavyycsrgdysnyayfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyq qkpgkvpk lliyaastlqsgvpsrfsgsgsgtdftlti sslqaedvavyycqqyystpltfgggtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay 1qmnnlktedtavyycv rhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvl 1031. CD70_28xCD3 bispecifically evqlvesggglvkpggslrlscaasgftfs

- 381 043309

-scFc cheskaya HLE molecule system fsgsgsgtdftlti sslqaedvavyycqqyystpltfgggtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay 1qmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvs sggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfIfppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspgKggggsggggsggggsggggsgg ggsggggsdkthtcppcpapellggpsvf1 fppkpkdtlmisrtpevtcvvvdvshedpe vkfnwyvdgvevhnaktkpce eqygstyrc vsvltvlhqdwlngkeykckvsnkalpapi ektiskakgqprepqvytlppsreemtknq vs1tclvkgfypsdiavewesngqpennyk ttppvldsdgsfflyskitvdksrwqqgnv fscsvmhealhnhytqkslslspgk 1032. CD70_29_CCx CD3-scFc VH CDR1 vyams 1033. CD70_29_CCx VH CDR2 tisgsggstfyaesvkg

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CD3-scFc 1034. CD70_29_CCx CD3-scFc VH CDR3 hdysnyayfdy 1035. CD70_29_CCx CD3-scFc VL CDR1 rasqsvrssyla 1036. CD70_29_CCx CD3-scFc VL CDR2 gassrat 1037. CD70_29_CCx CD3-scFc VL CDR3 qqygdlpft 1038. CD70_29_CCx CD3-scFc VH evqllesggglvqpggslrIscaasgftfs vyamswvrqapgkclewvstisgsggstfу aesvkgrftisrdnskntlylqmnrlraed tavyycarhdysnyayfdywgqgtlvtvss 1039. CD70_29_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgcgtkveik 1040. CD70_29_CCx CD3-scFc scFv evqllesggglvqpggslrIscaasgftfs vyamswvrqapgkclewvstisgsggstfу aesvkgrftisrdnskntlylqmnrlraed tavyycarhdysnyayfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv elk 1041. CD70_29_CCx CD3-scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs vyamswvrqapgkclewvstisgsggstfу aesvkgrftisrdnskntlylqmnrlraed tavyycarhdysnyayfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls

- 383 043309

caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisу waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapg tp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 1042. CD70_29_CCx CD3-scFc bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs vyamswvrqapgkclewvstisgsggstfу aesvkgrftisrdnskntlylqmnrlraed tavyycarhdysnyayfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisu waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlqgggdkthtcpp cpape11ggpsvfIfppk pkdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwq qgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpape11ggpsvf IfppkpkdtImisrtpevtcvvvdvshedp

- 384 043309

evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspg k 1043. CD70_29xCD3 -scFc VH evqllesggglvqpggslrIscaasgftfs vyamswvrqapgkglewvstisgsggstfу aesvkgrftisrdnskntlylqmnrlraed tavyycarhdysnyayfdywgqgtlvtvss 1044. CD70_29xCD3 -scFc VL eivltqspgtlslspgeratlscrasqsvr ssylawyqqkpgqaprlliygassratgip drfsgsgsgtdftltisrlepedfavyycq qygdlpftfgpgtkveik 1045. CD70_29xCD3 -scFc scFv evqllesggglvqpggslrIscaasgftfs vyamswvrqapgkglewvstisgsggstfу aesvkgrftisrdnskntlylqmnrlraed tavyycarhdysnyayfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eik 1046. CD70_29xCD3 -scFc bispecific molecule evqllesggglvqpggslrIscaasgftfs vyamswvrqapgkglewvstisgsggstfу aesvkgrftisrdnskntlylqmnrlraed tavyycarhdysnyayfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta у1qmnnlktedtavyycvrhgnfgnsyisy

- 385 043309

waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 1047. CD70_29xCD3 -scFc bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs vyamswvrqapgkglewvstisgsggstfу aesvkgrftisrdnskntlylqmnrlraed tavyycarhdysnyayfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkd tlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvf scsvmhealhnhytq kslslspgkggggsggggsggggsggggsg gggsggggsdkthtcppcpapelIggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqpre pqvytlppsreemtkn

- 386 043309

qvsltclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmheaIhnhytqkslslspgk 1048. CD70_30_CCx CD3-scFc VH CDR1 sygmh 1049. CD70_30_CCx CD3-scFc VH CDR2 visyegsnkyyaesvkg 1050. CD70_30_CCx CD3-scFc VH CDR3 gryygsgnynhgmdv 1051. CD70_30_CCx CD3-scFc VL CDR1 rasqsissyln 1052. CD70_30_CCx CD3-scFc VL CDR2 aasslqs 1053. CD70_30_CCx CD3-scFc VL CDR3 qqsystpft 1054. CD70_30_CCx CD3-scFc VH qvqlvesgggvvqpgrslrlscaasgfmfs sygmhwvrqapgkclewvavisyegsnkyy aesvkgrftisrdnskntlylqmnslraed tavyycargryygsgnynhgmdvwgqgttv tvss 1055. CD70_30_CCx CD3-scFc VL diqmtqspsslsasvgdrvtitcrasqsis sylnwyqqkpgkapklliyaasslqsgvps rfsgrgsgtdftltisslqpedfatyycqq systpftfgcgtkveik 1056. CD70_30_CCx CD3-scFc scFv qvqlvesgggvvqpgrslrlscaasgfmfs sygmhwvrqapgkclewvavisyegsnkyy aesvkgrftisrdnskntlylqmnslraed tavyycargryygsgnynhgmdvwgqgttv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqsis sylnwyqqkpg kapklliyaasslqsgvpsrfsgrgsgtdf tltisslqpedfatyycqqsystpftfgeg tkveik 1057. CD70_30_CCx CD3-scFc bispecifically cheskaya qvqlvesgggvvqpgrslrlscaasgfmfs sygmhwvrqapgkclewvavisyegsnkyy

- 387 043309

molecule aesvkgrftisrdnskntlylqmnslraed tavyycargryygsgnynhgmdvwgqgttv tvssggggsggggsggggsdiqmtqspssi sasvgdrvtitcrasqsissylnwyqqkpg kapklliyaasslqsgvpsrfsgrgsgtdf tltisslqpedfatyycqqsyst pftfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltc gsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 1058. CD70_30_CCx CD3-scFc bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgfmfs sygmhwvrqapgkclewvavisyegsnkyy aesvkgrftisrdnskntlylqmnslraed tavyycargryygsgnynhgmdvwgqgttv tvssggggsggggsggggsdiqmtqspssi sasvgdrvtitcrasqsiss ylnwyqqkpg kapklliyaasslqsgvpsrfsgrgsgtdf tltisslqpedfatyycqqsystpftfgeg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvr hgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIggps vfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln

- 388 043309

gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgKggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp s vfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdks rwq qgnvfscsvmhealhnhytqkslslspgk 1059. CD70_30xCD3 -scFc VH qvqlvesgggvvqpgrslrlscaasgfmfs sygmhwvrqapgkglewvavisyegsnkyy aesvkgrftisrdnskntlylqmnslraed tavyycargryygsgnynhgmdvwgqgttv tvss 1060. CD70_30xCD3 -scFc VL diqmtqspsslsasvgdrvtitcrasqsis sylnwyqqkpgkapklliyaasslqsgvps rfsgrgsgtdftltisslqpedfatyycqq systpftfgpgtkveik 1061. CD70_30xCD3 -scFc scFv qvqlvesgggvvqpgrslrlscaasgfmfs sygmhwvrqapgkglewvavisyegsnkyy aesvkgrftisrdnskntlylqmnslraed tavyycargryygsgnynhgmdvwgqgttv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqsis sylnwyqqkpg kapklliyaasslqsgvpsrfsgrgsgtdf tltisslqpedfatyycqqsystpftfgpg tkveik 1062. CD70_30xCD3 -scFc bispecific molecule qvqlvesgggvvqpgrslrlscaasgfmfs sygmhwvrqapgkglewvavisyegsnkyy aesvkgrftisrdnskntlylqmnslraed tavyycargryygsgnynhgmdvwgqgttv

- 389 043309

tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqsissylnwyqqkpg kapklliyaasslqsgvpsrfsgrgsgtdf tltisslqpedfatyycqqsystpftfgpg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqap gkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgv qpedeaey ycvlwysnrwvfgggtkltvl 1063. CD70_30xCD3 -scFc bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgfmfs sygmhwvrqapgkglewvavisyegsnkyy aesvkgrftisrdnskntlylqmnslraed tavyycargryygsgnynhgmdvwgqgttv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqsis sylnwyqqkpg kapklliyaasslqsgvpsrfsgrgsgtdf tltisslqpedfatyycqqsystpftfgpg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapell ggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytIppsreemtknqvsltclvkgfyps

-390 043309

diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgkggggsggggsggggsggg gsggggsggggsdkthteppepapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpce eqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 1064. CD70_31_CCx CD3-scFc VH CDR1 sygmh 1065. CD70_31_CCx CD3-scFc VH CDR2 vtwydasnkyygdavkg 1066. CD70_31_CCx CD3-scFc VH CDR3 dllrgvkgyamdv 1067. CD70_31_CCx CD3-scFc VL CDR1 rasqslrriyla 1068. CD70_31_CCx CD3-scFc VL CDR2 dvfdrat 1069. CD70_31_CCx CD3-scFc VL CDR3 qqysespft 1070. CD70_31_CCx CD3-scFc VH qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkclewvavtwydasnkyy gdavkgrftisrdnskntlylqmnslraed tavyycardllrgvkgyamdvwgqgttvtv ss 1071. CD70_31_CCx CD3-scFc VL eivltqspgtlslspgeratlscrasqslr riylawyqqkpgqaprlliydvfdratgip drfsgggsgtdftltisrlepedfavyycq qysespftfgcgtkvdik 1072. CD70_31_CCx CD3-scFc scFv qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkclewvavtwydasnkyy gdavkgrftisrdnskntlylqmnslraed

- 391 043309

tavyycardllrgvkgyamdvwgqgttvtv ssggggsggggsggggseivltqspgtlsl spgeratlscrasqslrriylawyqqkpgq aprlliydvfdratgipdrfsgggsgtdft Itisrlepedfavyycqqysespftfgcgt kvdik 1073. CD70_31_CCx CD3-scFc bispecific molecule qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkclewvavtwydasnkyy gdavkgrftisrdnskntlylqmnslraed tavyycardllrgvkgyamdvwgqgttvtv ssggggsggggsggggseivltqspgtlsl spgeratlscrasqslrriylawyq qkpgq aprlliydvfdratgipdrfsgggsgtdft Itisrlepedfavyycqqysespftfgcgt kvdiksggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavyycvrhgnfgn syi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvl 1074. CD70_31_CCx CD3-scFc bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkclewvavtwydasnkyy gdavkgrftisrdnskntlylqmnslraed tavyycardllrgvkgyamdvwgqgttvtv ssggggsggggsggggseivltqspgtlsl spgeratlscrasqslrriylawyq qkpgq aprlliydvfdratgipdrfsgggsgtdft Itisrlepedfavyycqqysespftfgcgt kvdiksggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavyycvrhgnfgn syi

- 392 043309

sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpapellggpsvfIfppk pkdtImisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsffl yskltvdksrwq qgnvfscsvmhealhnhy tqkslslspgKggggsggggsggggsgggg sggggsggggsdkthtcppcpapellggps vfIfppkpkdtImisrtpevtcvvvdvshe dpevkfnwyvdgvevhnaktkpceeqygst yrcvsvltvlhqdwlngkeykckvsnkalp apiek tiskakgqprepqvytlppsreemt knqvsltclvkgfypsdiavewesngqpen nykttppvldsdgsfflyskitvdksrwqq gnvfscsvmhealhnhytqkslslspgk 1075. CD70_31xCD3 -scFc VH qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkglewvavtwydasnkyy gdavkgrftisrdnskntlylqmnslraed tavyycardllrgvkgyamdvwgqgttvtv ss 1076. CD70_31xCD3 -scFc VL eivltqspgtlslspgeratlscrasqslr riylawyqqkpgqaprlliydvfdratgip drfsgggsgtdftltisrlepedfavyycq qysespftfgpgtkvdik 1077. CD70_31xCD3 -scFc scFv qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkglewvavtwydasnkyy gdavkgrftisrdnskntlylqmnslraed tavyycardllrgvkgyamdvwgqgttvtv ssggggsggggsggggseivltqspgtlsl

- 393 043309

spgeratlscrasqslrriylawyqqkpgq aprlliydvfdratgipdrfsgggsgtdft Itisrlepedfavyycqqysespftfgpgt kvdik 1078. CD70_31xCD3 -scFc bispecific molecule qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkglewvavtwydasnkyy gdavkgrftisrdnskntlylqmnslraed tavyycardllrgvkgyamdvwgqgttvtv ssggggsggggsggggseivltqspgtlsl spgeratlscrasqslrriylawyq qkpgq aprlliydvfdratgipdrfsgggsgtdft Itisrlepedfavyycqqysespftfgpgt kvdiksggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tayIqmnnlktedtavyycvrhgnfgn syi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvl 1079. CD70_31xCD3 -scFc bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkglewvavtwydasnkyy gdavkgrftisrdnskntlylqmnslraed tavyycardllrgvkgyamdvwgqgttvtv ssggggsggggsggggseivltqspgtlsl spgeratlscrasqslrriylawyq qkpgq aprlliydvfdratgipdrfsgggsgtdft Itisrlepedfavyycqqysespftfgpgt kvdiksggggsevqlvesggglvqpggslk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn tayIqmnnlktedtavyycvrhgnfgn syi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav

- 394 043309

tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpape11ggpsvfIfppkpkdtImisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcv svltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspgKggggsggggsggggsgggg sggggsggggsdktht cppcpapellggps vfIfppkpkdtImisrtpevtcvvvdvshe dpevkfnwyvdgvevhnaktkpceeqygst yrcvsvltvlhqdwlngkeykckvsnkalp apiektiskakgqprepqvytlppsreemt knqvsltclvkgfypsdiavewesngqpen nykttppvlds dgsfflyskitvdksrwqq gnvfscsvmhealhnhytqkslslspgk 1080. CD70_32_CCx CD3-scFc VH CDR1 sygis 1081. CD70_32_CCx CD3-scFc VH CDR2 wisayqgythyaqklqg 1082. CD70_32_CCx CD3-scFc VH CDR3 dyggndyygmdv 1083. CD70_32_CCx CD3-scFc VL CDR1 sgsssniginyvy 1084. CD70_32_CCx CD3-scFc VL CDR2 rsdqrps 1085. CD70_32_CCx CD3-scFc VL CDR3 aafdeslsgvv 1086. CD70_32_CCx CD3-scFc VH qvqlvqsgaevkkpgasvkvsckasgytft sygiswvrqapgqclewmgwisayqgythy aqklqgrvtmttdtststaymelrslrsdd tavyycardyggndyygmdvwgqgttvtvs

- 395 043309

S 1087. CD70_32_CCx CD3-scFc VL qsvltqppsasgtpgqrvtiscsgsssnig inyvywyqqlpgtapklliyrsdqrpsgvp drfsgsksgtsaslalsglrsedeadyyca afdesIsgvvfgcgtkltvl 1088. CD70_32_CCx CD3-scFc scFv qvqlvqsgaevkkpgasvkvsckasgytft sygiswvrqapgqclewmgwisayqgythy aqklqgrvtmttdtststaymelrslrsdd tavyycardyggndyygmdvwgqgttvtvs sggggsggggsggggsqsvltqppsasgtp gqrvtiscsgsssnigin yvywyqqlpgta pklliyrsdqrpsgvpdrfsgsksgtsasl alsglrsedeadyycaafdesIsgvvfgcg tkltvl 1089. CD70_32_CCx CD3-scFc bispecifically ical molecule qvqlvqsgaevkkpgasvkvsckasgytft sygiswvrqapgqclewmgwisayqgythy aqklqgrvtmttdtststaymelrslrsdd tavyycardyggndyygmdvwgqgttvtvs sggggsggggsggggsqsvltqppsasgtp gqrvtiscsgsssnigin yvywyqqlpgta pklliyrsdqrpsgvpdrfsgsksgtsasl alsglrsedeadyycaafdesIsgvvfgcg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedta vyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 1090. CD70_32_CCx CD3-scFc bispecific HLE molecule qvqlvqsgaevkkpgasvkvsckasgytft sygiswvrqapgqclewmgwisayqgythy aqklqgrvtmttdtststaymelrslrsdd tavyycardyggndyygmdvwgqgttvtvs

- 396 043309

sggggsggggsggggsqsvltqppsasgtp gqrvtiscsgsssniginyvywyqqlpgta pklliyrsdqrpsgvpdrfsgsksgtsasl alsglrsedeadyycaafdeslsgvvfgeg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqap gkglewv arirskynnyatyyadsvkdrftisrddsk ntay1qmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsg vqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsre emtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgKggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtImisrtpevtcvvvdvsh edpev kfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 1091. CD70_32xCD3 -scFc VH qvqlvqsgaevkkpgasvkvsckasgytft sygiswvrqapgqglewmgwisayqgythy aqklqgrvtmttdtststaymelrslrsdd tavyycardyggndyygmdvwgqgttvtvs s 1092. CD70_32xCD3 VL qsvltqppsasgtpgqrvtiscsgsssnig

- 397 043309

-scFc inyvywyqqlpgtapklliyrsdqrpsgvp drfsgsksgtsaslalsglrsedeadyyca afdesIsgvvfgggtkltvl 1093. CD70_32xCD3 -scFc scFv qvqlvqsgaevkkpgasvkvsckasgytft sygiswvrqapgqglewmgwisayqgythy aqklqgrvtmttdtststaymelrslrsdd tavyycardyggndyygmdvwgqgttvtvs sggggsggggsggggsqsvltqppsasgtp gqrvtiscsgsssnigin yvywyqqlpgta pklliyrsdqrpsgvpdrfsgsksgtsasl alsglrsedeadyycaafdesIsgvvfggg tkltvl 1094. CD70_32xCD3 -scFc bispecific molecule qvqlvqsgaevkkpgasvkvsckasgytft sygiswvrqapgqglewmgwisayqgythy aqklqgrvtmttdtststaymelrslrsdd tavyycardyggndyygmdvwgqgttvtvs sggggsggggsggggsqsvltqppsasgtp gqrvtiscsgsssnigin yvywyqqlpgta pklliyrsdqrpsgvpdrfsgsksgtsasl alsglrsedeadyycaafdesIsgvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavy ycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 1095. CD70_32xCD3 -scFc bispecific HLE molecule qvqlvqsgaevkkpgasvkvsckasgytft sygiswvrqapgqglewmgwisayqgythy aqklqgrvtmttdtststaymelrslrsdd tavyycardyggndyygmdvwgqgttvtvs sggggsggggsggggsqsvltqppsasgtp gqrvtiscsgsssnigin yvywyqqlpgta

- 398 043309

pklliyrsdqrpsgvpdrfsgsksgtsasl alsglrsedeadyycaafdeslsgvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy is ywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpape11ggpsvfIfppk pkdtImisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqggn vfscsvmhealhnh ytqkslslspgKggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtImisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papie ktiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 1096. CD70_33_CCx CD3-scFc VH CDR1 yygmh 1097. CD70_33_CCx CD3-scFc VH CDR2 viwydasnkyyadavkg 1098. CD70_33_CCx CD3-scFc VH CDR3 dremgsrgdfdy 1099. CD70_33_CCx CD3-scFc VL CDR1 rasqginnyla

- 399 043309

1100. CD70_33_CCx CD3-scFc VL CDR2 avsilqs 1101. CD70_33_CCx CD3-scFc VL CDR3 qqynfypfs 1102. CD70_33_CCx CD3-scFc VH gaglvesgggvvgpgrslrlscaasgftfs yygmhwvrgapgkclewvaviwydasnkyy adavkgrftisrdnskntlylgmnslraed tavyycardremgsrgdfdywgggtlvtvs s 1103. CD70_33_CCx CD3-scFc VL digmtgspsslsasvgdrvtitcrasqgin nylawfggkpgkapksliyavsilgsgvps kfsgsgsgtdftltisnlgpedfatyycgg ynfypfsfgcgtkvdik 1104. CD70_33_CCx CD3-scFc scFv gaglvesgggvvgpgrslrlscaasgftfs yygmhwvrgapgkclewvaviwydasnkyy adavkgrftisrdnskntlylgmnslraed tavyycardremgsrgdfdywgggtlvtvs sggggsggggsggggsdigmtgspss1sas vgdrvtitcrasqginnylawfqqkp gkap ksliyavsilgsgvpskfsgsgsgtdftit isnlqpedfatyycqqynfypfsfgcgtkv dik 1105. CD70_33_CCx CD3-scFc bispecific molecule qaqlvesgggvvqpgrslrlscaasgftfs yygmhwvrgapgkclewvaviwydasnkyy adavkgrftisrdnskntlylqmnslraed tavyycardremgsrgdfdywgqgtlvtvs sggggsggggsggggsdiqmtqspsslsas vgdrvtitcrasqginnylawfq qkpgkap ksliyavsilgsgvpskfsgsgsgtdftit isnlqpedfatyycgqynfypfsfgcgtkv diksggggsevglvesggglvgpggsIkis caasgftfnkyamnwvrgapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylgmnnlktedtavyycvrhgnfgnsy isy waywgggtlvtvssggggsggggsggggsg

-400043309

tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 1106. CD70_33_CCx CD3-scFc bispecific HLE molecule qaqlvesgggvvqpgrsirIscaasgftfs yygmhwvrqapgkclewvaviwydasnkyy adavkgrftisrdnskntlylqmnslraed tavyycardremgsrqdfdywgqgtlvtvs sggggsggggsggggsdiqmtqspsslsas vgdrvtitcrasqginnylawfq qkpgkap ksliyavsilqsgvpskfsgsgsgtdftit isnlqpedfatyycqqynfypfsfgcgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta y1qmnnlktedtavyycvrhgnfgnsy isy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppk pkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwq qgnvfscsvmhealhnhytq kslslspgKggggsgqggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap i ektiskakgqprepqvytlppsreemtkn qvsltclvkgfypsdiavewesngqpenny

- 401 043309

kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 1107. CD70_33xCD3 -scFc VH qaqlvesgggvvqpgrslrlscaasgftfs yygmhwvrqapgkglewvaviwydasnkyy adavkgrftisrdnskntlylqmnslraed tavyycardremgsrgdfdywgqgtlvtvs s 1108. CD70_33xCD3 -scFc VL diqmtqspsslsasvgdrvtitcrasqgin nylawfqqkpgkapksliyavsilqsgvps kfsgsgsgtdftltisnlqpedfatyycqq ynfypfsfgqgtkvdik 1109. CD70_33xCD3 -scFc scFv qaqlvesgggvvqpgrslrlscaasgftfs yygmhwvrqapgkglewvaviwydasnkyy adavkgrftisrdnskntlylqmnslraed tavyycardremgsrgdfdywgqgtlvtvs sggggsggggsggggsdiqmtqspsslsas vgdrvtitcrasqginnylawfq qkpgkap ksliyavsilqsgvpskfsgsgsgtdftit isnlqpedfatyycqqynfypfsfgqgtkv dik 1110. CD70_33xCD3 -scFc bispecific molecule qaqlvesgggvvqpgrslrlscaasgftfs yygmhwvrqapgkglewvaviwydasnkyy adavkgrftisrdnskntlylqmnslraed tavyycardremgsrgdfdywgqgtlvtvs sggggsggggsggggsdiqmtqspsslsas vgdrvtitcrasqginnylawfq qkpgkap ksliyavsilqsgvpskfsgsgsgtdftit isnlqpedfatyycqqynfypfsfgqgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsy isy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp

- 402 043309

arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl 1111. CD70_33xCD3 -scFc bispecific HLE molecule qaqlvesgggvvqpgrsirIscaasgftfs yygmhwvrqapgkglewvaviwydasnkyy adavkgrftisrdnskntlylqmnslraed tavyycardremgsrgdfdywgqgtlvtvs sggggsggggsggggsdiqmtqspsslsas vgdrvtitcrasqginnylawfq qkpgkap ksliyavsilqsgvpskfsgsgsgtdftit isnlqpedfatyycqqynfypfsfgqgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsy isy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppk pkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwq qgnvfscsvmhealhnhytq kslslspgKggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iek tiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk

- 403 043309

1112. CD70_34_CCx CD3-scFc VH CDR1 gf yws 1113. CD70_34_CCx CD3-scFc VH CDR2 eiyhsghatnnpslks 1114. CD70_34_CCx CD3-scFc VH CDR3 ggnsgyifdy 1115. CD70_34_CCx CD3-scFc VL CDR1 rtsqyigryln 1116. CD70_34_CCx CD3-scFc VL CDR2 gastlqq 1117. CD70_34_CCx CD3-scFc VL CDR3 qqtystprt 1118. CD70_34_CCx CD3-scFc VH qvqlqqwgagllkpsetlsltcavyggsfs gfywswirqppgkclewigeiyhsghatnn pslksrvtisldtsknqfslklnsvtaadt avyуcarggnsgyifdywgqgtlvtvss 1119. CD70_34_CCx CD3-scFc VL dvqmtqspsslsasvgdrvtitcrtsqyig rylnwyqqkpgkapkvliygastlqqgvps rfsgsgsgtdftltitslqpedfasyycqq tystprtfgcgtkveik 1120. CD70_34_CCx CD3-scFc scFv qvqlqqwgagllkpsetlsltcavyggsfs gfywswirqppgkclewigeiyhsghatnn pslksrvtisldtsknqfslklnsvtaadt avyycarggnsgyifdywgqgtlvtvssgg ggsggggsggggsdvqmtqspsslsasvgd rvtitcrtsqyigrylnwyq qkpgkapkvl iygastlqqgvpsrfsgsgsgtdftltits Iqpedfasyycqqtуstprtfgcgtkveik 1121. CD70_34_CCx CD3-scFc bispecific molecule qvqlqqwgagllkpsetlsltcavyggsfs gfywswirqppgkclewigeiyhsghatnn pslksrvtisldtsknqfslklnsvtaadt avyycarggnsgyifdywgqgtlvtvssgg ggsggggsggggsdvqmtqspsslsasvgd rvtitcrtsqyigrylnwyq qkpgkapkvl iygastlqqgvpsrfsgsgsgtdftltits

- 404 043309

Iqpedfasyycqqtystprtfgcgtkveik sggggsevqlvesggglvqpggsIkiscaa sgftfnkyamnwvrqapgkglewvarirsk ynnyatyyadsvkdrftisrddskntaylq mnnlktedtavyycvrhgnfgnsyisyway wgqgtlvtvssggggsggggsggggsqt vv tqepsltvspggtvtltcgsstgavtsgny pnwvqqkpgqaprgliggtkflapgtparf sgsllggkaaltlsgvqpedeaeyycvlwy snrwvfgggtkitvl 1122. CD70_34_CCx CD3-scFc bispecific HLE molecule qvqlqqwgagllkpsetlsltcavyggsfs gfywswirqppgkclew!gelyhsghatnn pslksrvtisldtsknqfslklnsvtaadt avyycarggnsgyifdywgqgtlvtvssgg ggsggggsggggsdvqmtqspsslsasvgd rvtitcrtsqyigrylnwy qqkpgkapkvl iygastlqqgvpsrfsgsgsgtdftltits Iqpedfasyycqqtystprtfgcgtkveik sggggsevqlvesggglvqpggsIkiscaa sgftfnkyamnwvrqapgkglewvarirsk ynnyatyyadsvkdrftisrddskntaylq mnnlktedtavyycv rhgnfgnsyisyway wgqgtlvtvssggggsggggsggggsqtvv tqepsltvspggtvtltcgsstgavtsgny pnwvqqkpgqaprgliggtkflapgtparf sgsllggkaaltlsgvqpedeaeyycvlwy snrwvfgggtkitvlggggdkthtcppcpa pellggpsv fIfppkpkdtlmisrtpevtc vvvdvshedpevkfnwyvdgvevhnaktkp ceeqygstyrcvsvltvlhqdwlngkeykc kvsnkalpapiektiskakgqprepqvytl ppsreemtknqvsltclvkgfypsdiavew esngqpennykttppvldsdgsfflyskit vdksrwq qgnvfscsvmhealhnhytqksl slspgKggggsggggsggggsggggsgggg

- 405 043309

sggggsdkthtcppcpapellggpsvfIfp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpceeqygstyrcvs vltvlhqdwlngkeykckvsnkalpapiek tiskakgqprepqvytlppsreemtknqvs Itclvkgfypsdiavewesngqpenny ktt ppvldsdgsfflyskitvdksrwqqgnvfs csvmheaIhnhytqkslslspgk 1123. CD70_34xCD3 -scFc VH qvqlqqwgagllkpsetlsltcavyggsfs gfywswirqppgkglewigeiyhsghatnn pslksrvtisldtsknqfslklnsvtaadt avyycarggnsgyifdywgqgtlvtvss 1124. CD70_34xCD3 -scFc VL dvqmtqspsslsasvgdrvtitcrtsqyig rylnwyqqkpgkapkvliygastlqqgvps rfsgsgsgtdftltitslqpedfasyycqq tystprtfgqgtkveik 1125. CD70_34xCD3 -scFc scFv qvqlqqwgagllkpsetlsltcavyggsfs gfywswirqppgkglewigeiyhsghatnn pslksrvtisldtsknqfslklnsvtaadt avyycarggnsgyifdywgqgtlvtvssgg ggsggggsggggsdvqmtqspsslsasvgd rvtitcrtsqyigrylnwyq qkpgkapkvl iygastlqqgvpsrfsgsgsgtdftltits Iqpedfasyycqqtуstprtfgqgtkveik 1126. CD70_34xCD3 -scFc bispecifically ical molecule qvqlqqwgagllkpsetlsltcavyggsfs gfywswirqppgkglewigeiyhsghatnn pslksrvtisldtsknqfslklnsvtaadt avyycarggnsgyifdywgqgtlvtvssgg ggsggggsggggsdvqmtqspsslsasvgd rvtitcrtsqyigrylnwyq qkpgkapkvl iygastlqqgvpsrfsgsgsgtdftltits Iqpedfasyycqqtуstprtfgqgtkveik sggggsevqlvesggglvqpggsIkiscaa sgftfnkyamnwvrqapgkglewvarirsk ynnyatyyadsvkdrftisrddskntaylq

- 406 043309

mnnlktedtavyycvrhgnfgnsyisyway wgqgtlvtvssggggsggggsggggsqtvv tqepsltvspggtvtltcqsstgavtsgny pnwvqqkpgqaprgliggtkflapgtparf sgsllggkaaltlsgvqpedeaeyycvlwy snrwvfgqgtkltvl 1127. CD70_34xCD3 -scFc bispecific HLE molecule qvqlqqwgagllkpsetlsltcavyggsfs gfywswirqppgkglewigeiyhsghatnn pslksrvtisldtsknqfslklnsvtaadt avyycarggnsgyifdywgqgtlvtvssgg ggsggggsggggsdvqmtqspsslsasvgd rvtitcrtsqyigrylnwyq qkpgkapkvl iygastlqqgvpsrfsgsgsgtdftltits Iqpedfasyycqqtystprtfgqgtkveik sggggsevqlvesggglvqpggsIkiscaa sgftfnkyamnwvrqapgkglewvarirsk ynnyatyyadsvkdrftisrddskntaylq mnnlktedtavyycvr hgnfgnsyisyway wgqgtlvtvssggggsggggsggggsqtvv tqepsltvspggtvtltcqsstgavtsgny pnwvqqkpgqaprgliggtkflapgtparf sgsllggkaaltlsgvqpedeaeyycvlwy snrwvfgqgtkltvlgggqdkthtcppcpa pellgg psvfIfppkpkdtImisrtpevtc vvvdvshedpevkfnwyvdgvevhnaktkp ceeqygstyrcvsvltvlhqdwlngkeykc kvsnkalpapiektiskakgqprepqvytl ppsreemtknqvsltclvkgfypsdiavew esngqpennykttppvldsdgsfflysklt vdksr wqqgnvfscsvmhealhnhytqksl slspgkggggsggggsggggsggggsgggg sggggsdkthtcppcpapellggpsvfIfp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpceeqygstyrcvs vltvlhqdwlngkeykckvsnkalpapiek

- 407 043309

tiskakgqprepqvytlppsreemtknqvs itclvkgfypsdiavewesngqpennyktt ppvldsdgsfflyskitvdksrwqqgnvfs csvmhealhnhytqkslslspgk 1128. CD70_35_CCx CD3-scFc VH CDR1 tygmh 1129. CD70_35_CCx CD3-scFc VH CDR2 viwyegsnkyygesvkg ISO. CD70_35_CCx CD3-scFc VH CDR3 dnshyyygmdv 1131. CD70_35_CCx CD3-scFc VL CDR1 tgsssnigagydvn 1132. CD70_35_CCx CD3-scFc VL CDR2 vnnnrps 1133. CD70_35_CCx CD3-scFc VL CDR3 qsydtslsasv 1134. CD70_35_CCx CD3-scFc VH qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkclewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyyqmdvwgqgttvtvss 1135. CD70_35_CCx CD3-scFc VL qsvltqppsvsgapgqrvtisctgsssnig agydvnwyqqfpgtapklliyvnnnrpsgv pdrfsgstsgtsaslaitglqaedeadyyc qsydtslsasvfgcgtrltvl 1136. CD70_35_CCx CD3-scFc scFv qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkclewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyyqmdvwgqgttvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagy dvnwyqqfpgta pklliyvnnnrpsgvpdrfsgstsgtsasl aitglqaedeadyycqsydtslsasvfgcg trltvl 1137. CD70_35_CCx CD3-scFc bispecifically cheskaya qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkclewvaviwyegsnkyy

-408 043309

molecule gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgttvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagydvnwyqqfpgta pklliyvnnnrpsgvpdrfsgstsgtsasl aitglqaedeady ycqsydtslsasvfgeg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltv spggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 1138. CD70_35_CCx CD3-scFc bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgftfs tygmhwvrqapgkclewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgttvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagy dvnwyqqfpgta pklliyvnnnrpsgvpdrfsgstsgtsasl aitglqaedeadyycqsydtslsasvfgeg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlk tedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht c ppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln

-409043309

gkeykckvsnkalpapiektiskakgqpre pqvytIppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgKggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp s vfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdks rwq qgnvfscsvmhealhnhytqkslslspgk 1139. CD70_35xCD3 -scFc VH qvqlvesgggvvqpgrslrlscaasgftfs tygmhwvrqapgkglewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgttvtvss 1140. CD70_35xCD3 -scFc VL qsvltqppsvsgapgqrvtisctgsssnig agydvnwyqqfpgtapklliyvnnnnrpsgv pdrfsgstsgtsaslaitglqaedeadyyc qsydtslsasvfgggtrltvl 1141. CD70_35xCD3 -scFc scFv qvqlvesgggvvqpgrslrlscaasgftfs tygmhwvrqapgkglewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgttvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagy dvnwyqqfpgta pklliyvnnnrpsgvpdrfsgstsgtsasl aitglqaedeadyycqsydtslsasvfggg trltvl 1142. CD70_35xCD3 -scFc bispecific molecule qvqlvesgggvvqpgrslrlscaasgftfs tygmhwvrqapgkglewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgttvtvss ggggsggggsggggsqsvltqppsvsgapg

- 410 043309

qrvtisctgsssnigagydvnwyqqfpgta pklliyvnnnrpsgvpdrfsgstsgtsasl aitglqaedeadyycqsydtslsasvfggg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkd rftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfg ggtkltvl 1143. CD70_35xCD3 -scFc bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgftfs tygmhwvrqapgkglewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgttvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagydvnwyqqfpgta pklliyvnnnrpsgvpdrfsgstsgtsasl aitglqaedeadyycqsydtslsasvfggg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff

-411 043309

lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgKggggsggggsggggsggg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtImisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhq dwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 1144. CD70_36_CCx CD3-scFc VH CDR1 tygmh 1145. CD70_36_CCx CD3-scFc VH CDR2 viwyegsnkyygesvkg 1146. CD70_36_CCx CD3-scFc VH CDR3 dnshyyygmdv 1147. CD70_36_CCx CD3-scFc VL CDR1 tgsssnigagydvn 1148. CD70_36_CCx CD3-scFc VL CDR2 vnnnrps 1149. CD70_36_CCx CD3-scFc VL CDR3 qsyetslsasv 1150. CD70_36_CCx CD3-scFc VH qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkclewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgtlvtvss 1151. CD70_36_CCx CD3-scFc VL qsvltqppsvsgapgqrvtisctgsssnig agydvnwyqqlpgtapklliyvnnnrpsgv pdrfsgsksgtsaslaitglqaedeadyyc qsyetslsasvfgcgtrltvl 1152. CD70_36_CCx CD3-scFc scFv qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkclewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgtlvtvss ggggsggggsggggsqsvltqppsvsgapg

- 412 043309

qrvtisctgsssnigagydvnwyqqlpgta pklliyvnnnrpsgvpdrfsgsksgtsasl aitglqaedeadyycqsyetslsasvfgeg trltvl 1153. CD70_36_CCx CD3-scFc bispecific molecule qvqlvesgggvvqpgrslrlscaasgftfs tygmhwvrqapgkclewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgtlvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagyd vnwyqqlpgta pklliyvnnnrpsgvpdrfsgsksgtsasl aitglqaedeadyycqsyetslsasvfgeg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 1154. CD70_36_CCx CD3-scFc bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgftfs tygmhwvrqapgkclewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgtlvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagyd vnwyqqlpgta pklliyvnnnrpsgvpdrfsgsksgtsasl aitglqaedeadyycqsyetslsasvfgeg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga

- 413 043309

vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvf1fppkpkdtImisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygs tyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgKggggsggggsggggsggg gsggggsggggsdk thtcppcpapellggp svf1fppkpkdtImisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlhqdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsltclvkgfypsdiavewesngqpe nnyktt ppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 1155. CD70_36xCD3 -scFc VH qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkglewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgtlvtvss 1156. CD70_36xCD3 -scFc VL qsvltqppsvsgapgqrvtisctgsssnig agydvnwyqqlpgtapklliyvnnnnrpsgv pdrfsgsksgtsaslaitglqaedeadyyc qsyetslsasvfgggtrltvl 1157. CD70_36xCD3 -scFc scFv qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkglewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgtlvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagyd vnwyqqlpgta pklliyvnnnrpsgvpdrfsgsksgtsasl aitglqaedeadyycqsyetslslasvfggg

- 414 043309

trltvl 1158. CD70_36xCD3 -scFc bispecific molecule qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkglewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgtlvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagyd vnwyqqlpgta pklliyvnnnrpsgvpdrfsgsksgtsasl aitglqaedeadyycqsyetslsasvfggg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 1159. CD70_36xCD3 -scFc bispecific HLE molecule qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkglewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgtlvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagyd vnwyqqlpgta pklliyvnnnrpsgvpdrfsgsksgtsasl aitglqaedeadyycqsyetslsasvfggg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht

- 415 043309

cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsItclvkgfyps diavewesngqpennykttppvldsd gsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspgKggggsggggsggggsgg gsggggsggggsdkthtcppcpapellggp svfIfppkpkdtlmisrtpevtcvvvdvsh edpevkfnwyvdgvevhnaktkpceeqygs tyrcvsvltvlh qdwlngkeykckvsnkal papiektiskakgqprepqvytlppsreem tknqvsItclvkgfypsdiavewesngqpe nnykttppvldsdgsfflyskitvdksrwq qgnvfscsvmhealhnhytqkslslspgk 1160. CD70_37_CCx CD3-scFc VH CDR1 sgvyyws 1161. CD70_37_CCx CD3-scFc VH CDR2 yiyysgstsynpslks 1162. CD70_37_CCx CD3-scFc VH CDR3 sgysyalfdy 1163. CD70_37_CCx CD3-scFc VL CDR1 rasqsvdryfn 1164. CD70_37_CCx CD3-scFc VL CDR2 aasslqs 1165. CD70_37_CCx CD3-scFc VL CDR3 qqsystpwt 1166. CD70_37_CCx CD3-scFc VH qmqlqesgpglvkpsetlsltctvsggsie sgvyywswirqppgkclewigyiyysgsts ynpslksrltmsvdtsknqfslklssvtaa dtavyycarsgysyalfdywgqgtlvtvss 1167. CD70_37_CCx CD3-scFc VL diqmtqspsslsaslgdrvtitcrasqsvd ryfnwyqqkpgkapkvlifaasslqsgvps rfsgsgsgtdftltisslqpedfatyycqq

- 416 043309

systpwtfgcgtkvevk 1168. CD70_37_CCx CD3-scFc scFv qmqlqesgpglvkpsetlsltctvsggsie sgvyywswirqppgkclewigyiyysgsts ynpsIksrItmsvdtsknqfslklssvtaa dtavyycarsgysyalfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasl gdrvtitcrasqsvdry fnwyqqkpgkapk vlifaasslqsgvpsrfsgsgsgtdftlti sslqpedfatyycqqsystpwtfgcgtkve vk 1169. CD70_37_CCx CD3-scFc bispecific molecule qmqlqesgpglvkpsetlsltctvsggsie sgvyywswirqppgkclewigyiyysgsts ynpslksrItmsvdtsknqfslklssvtaa dtavyycarsgysyalfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasl gdrvtitcrasqsvdry fnwyqqkpgkapk vlifaasslqsgvpsrfsgsgsgtdftlti sslqpedfatyycqqsystpwtfgcgtkve vksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyyc vrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtItcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvl 1170. CD70_37_CCx CD3-scFc bispecific HLE molecule qmqlqesgpglvkpsetlsltctvsggsie sgvyywswirqppgkclewigyiyysgsts ynpslksrItmsvdtsknqfslklssvtaa dtavyycarsgysyalfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasl gdrvtitcrasqsvdry fnwyqqkpgkapk vlifaasslqsgvpsrfsgsgsgtdftlti sslqpedfatyycqqsystpwtfgcgtkve

- 417 043309

vksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfIfppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvl hqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgfypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspgKggggsggggsggggsggggsgg ggsggggsdkthtcppcpapellggps vf1 fppkpkdtlmisrtpevtcvvvdvshedpe vkfnwyvdgvevhnaktkpceeqygstyrc vsvltvlhqdwlngkeykckvsnkalpapi ektiskakgqprepqvytlppsreemtknq vsItclvkgfypsdiavewesngqpennyk ttppvldsdgsfflyskitvdksrwqq gnv fscsvmhealhnhytqkslslspgk 1171. CD70_37xCD3 -scFc VH qmqlqesgpglvkpsetlsltctvsggsie sgvyywswirqppgkglewigyiyysgsts ynpslksrltmsvdtsknqfslklssvtaa dtavyycarsgysyalfdywgqgtlvtvss 1172. CD70_37xCD3 -scFc VL diqmtqspsslsaslgdrvtitcrasqsvd ryfnwyqqkpgkapkvlifaasslqsgvps rfsgsgsgtdftltisslqpedfatyycqq systpwtfgqgtkvevk 1173. CD70_37xCD3 -scFc scFv qmqlqesgpglvkpsetlsltctvsggsie sgvyywswirqppgkglewigyiyysgsts

- 418 043309

ynpslksrltmsvdtsknqfslklssvtaa dtavyycarsgysyalfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasl gdrvtitcrasqsvdryfnwyqqkpgkapk vlifaasslqsgvpsrfsgsgsgtdftlti sslqpedfatyycqq systpwtfgqgtkve vk 1174. CD70_37xCD3 -scFc bispecific molecule qmqlqesgpglvkpsetlsltctvsggsie sgvyywswirqppgkglewigyiyysgsts ynpslksrltmsvdtsknqfslklssvtaa dtavyycarsgysyalfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasl gdrvtitcrasqsvdry fnwyqqkpgkapk vlifaasslqsgvpsrfsgsgsgtdftlti sslqpedfatyycqqsystpwtfgqgtkve vksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyyc vrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvl 1175. CD70_37xCD3 -scFc bispecific HLE molecule qmqlqesgpglvkpsetlsltctvsggsie sgvyywswirqppgkglewigyiyysgsts ynpslksrltmsvdtsknqfslklssvtaa dtavyycarsgysyalfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasl gdrvtitcrasqsvdry fnwyqqkpgkapk vlifaasslqsgvpsrfsgsgsgtdftlti sslqpedfatyycqqsystpwtfgqgtkve vksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay

- 419 043309

Iqmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvlggggdkthtcppc papelIggpsvfIfppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspgKggggsggggsggggsggggsgg ggsggggsdkthtcppcpapelIggpsvf1 fppkpkdtlmisrtpevtcvvvdvshedpe vkfnwyvdgvevhnaktkpce eqygstyrc vsvltvlhqdwlngkeykckvsnkalpapi ektiskakgqprepqvytlppsreemtknq vsltclvkgfypsdiavewesngqpennyk ttppvldsdgsfflyskitvdksrwqqgnv fscsvmhealhnhytqkslslspgk 1176. CD70_38_CD3-scFc CCx VH CDR1 sggyyws 1177. CD70_38_CD3-scFc CCx VH CDR2 yifysgstdynpslks 1178. CD70_38_CD3-scFc CCx VH CDR3 sgysyalfda 1179. CD70_38_CD3-scFc CCx VL CDR1 rasqfigryfn 1180. CD70_38_CD3-scFc CCx VL CDR2 aesslqs 1181. CD70_38_CD3-scFc CCx VL CDR3 qqsystpwt

- 420 043309

1182. CD70_38_CCx CD3-scFc VH qvqlqesgpglvkpsqtlsltctvsgdsii sggyywswirqppgkclewigyifysgstd ynpslksrvtisvdtsknqfslklssvtaa dtavyycarsgysyalfdawgqgtlvtvss 1183. CD70_38_CCx CD3-scFc VL diqmtqspsslsasvgdrvtiscrasqfig ryfnwyqqkpgkapkvliyaesslqsgvps rfsgsgsgteftltisslqpedfatyycqq systpwtfgcgtkveik 1184. CD70_38_CCx CD3-scFc scFv qvqlqesgpglvkpsqtlsltctvsgdsii sggyywswirqppgkclewigyifysgstd ynpslksrvtisvdtsknqfslklssvtaa dtavyycarsgysyalfdawgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtiscrasqfigryfnwy qqkpgkapk vliyaesslqsgvpsrfsgsgsgteftlti sslqpedfatyycqqsystpwtfgcgtkve ik 1185. CD70_38_CCx CD3-scFc bispecific molecule qvqlqesgpglvkpsqtlsltctvsgdsii sggyywswirqppgkclewigyifysgstd ynpslksrvtisvdtsknqfslklssvtaa dtavyycarsgysyalfdawgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtiscrasqfigryfnwy qqkpgkapk vliyaesslqsgvpsrfsgsgsgteftlti sslqpedfatyycqqsystpwtfgcgtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrh gnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvl 1186. CD70_38_CCx bispecifically qvqlqesgpglvkpsqtlsltctvsgdsii

- 421 043309

CD3-scFc cheskaya HLE molecule sggyywswirqppgkclewigyifysgstd ynpslksrvtisvdtsknqfslklssvtaa dtavyycarsgysyalfdawgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtiscrasqfigryfnwyqqkpgkapk vliyaesslqsgvpsrfsgsgs gteftlti sslqpedfatyycqqsystpwtfgcgtkve iksggggsevqlvesgggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay 1qmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsgg ggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltv!ggggdkthtcppc papellggpsvfIfppkpkdtImisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspgKggggsggggsggggsggggsgg ggsggggsdkthtcppcpapellggpsvf! fppkpkdtlmisrtpevtcvvvdvshedpe vkfnwyvdgvevhnaktkpceeqygstyrc vsvltvlhqdwlngkeykckvsnkalpapi ektiskakgqprepqvytlppsreemtknq vsltclvkgfypsdiavewesngqpennyk ttppvldsdgsfflyskitvdksrwqqgnv fscsvmhealhnhytqkslslspgk 1187. CD70_38xCD3 -scFc VH qvqlqesgpglvkpsqtlsltctvsgdsii sggyywswirqppgkglewigyifysgstd ynpslksrvtisvdtsknqfslklssvtaa

- 422 043309

dtavyycarsgysyalfdawgqgtlvtvss 1188. CD70_38xCD3 -scFc VL diqmtqspsslsasvgdrvtiscrasqfig ryfnwyqqkpgkapkvliyaesslqsgvps rfsgsgsgteftltisslqpedfatyycqq systpwtfgqgtkveik 1189. CD70_38xCD3 -scFc scFv qvqlqesgpglvkpsqtlsltctvsgdsii sggyywswirqppgkglewigyifysgstd ynpslksrvtisvdtsknqfslklssvtaa dtavyycarsgysyalfdawgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtiscrasqfigryfnwy qqkpgkapk vliyaesslqsgvpsrfsgsgsgteftlti sslqpedfatyycqqsystpwtfgqgtkve ik 1190. CD70_38xCD3 -scFc bispecifically ical molecule qvqlqesgpglvkpsqtlsltctvsgdsii sggyywswirqppgkglewigyifysgstd ynpslksrvtisvdtsknqfslklssvtaa dtavyycarsgysyalfdawgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtiscrasqfigryfnwy qqkpgkapk vliyaesslqsgvpsrfsgsgsgteftlti sslqpedfatyycqqsystpwtfgqgtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrh gnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvl 1191. CD70_38xCD3 -scFc bispecific HLE molecule qvqlqesgpglvkpsqtlsltctvsgdsii sggyywswirqppgkglewigyifysgstd ynpslksrvtisvdtsknqfslklssvtaa dtavyycarsgysyalfdawgqgtlvtvss

- 423 043309

ggggsggggsggggsdiqmtqspsslsasv gdrvtiscrasqfigryfnwyqqkpqkapk vliyaesslqsgvpsrfsgsgsgteftlti sslqpedfatyycqqsystpwtfgqgtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapg kglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspqgtvtltcgsstgavtsq nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsg vqpedeaeyycvl wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfifppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtkn qvsltclvkgfypsdiav ewesngqpennykttppvldsdgsfflysk itvdksrwqqgnvfscsvmhealhnhytqk slslspgKggggsggggsggggsggggsgg ggsggggsdkthtcppcpapellggpsvf1 fppkpkdtimisrtpevtcvvvdvshedpe vkfnwyvdgve vhnaktkpceeqygstyrc vsvltvlhqdwlngkeykckvsnkalpapi ektiskakgqprepqvytlppsreemtknq vsltclvkgfypsdiavewesngqpennyk ttppvldsdgsfflyskitvdksrwqqgnv fscsvmhealhnhytqkslslspgk 1192. CD70_l_CCxC D3scFc_delGK bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvsvisgsggrpny aesvkgrftisrdnskntlylqmnslrded tavyycakvdysnylffdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp gegatlscragqsvrssylgwyqqk pgqap

- 424 043309

rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspptfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtl misrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utIppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscs vmhealhnhytq kslslspggggsggggsggggsggggsgg gsggggsdkthteppepapelggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlpps reemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1193. CD70_lxCD3scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsvisgsggrpny aesvkgrftisrdnskntlylqmnslrded tavyycakvdysnylffdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp gegatlscragqsvrssylgwyqqkp gqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspptfgggtkl

- 425 043309

eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnyp nwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlh qdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapell ggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrw qqgnvf scsvmhealhnhytqkslslspgk 1194. CD70_2_CCxC D3scFc_delGK bispecifically cheskaya HLE molecule evqllesggglvqpggslklscaasgftfs iyamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap r lliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari

- 426 043309

rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaey ycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkpkdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknq vsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpape11ggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvev hnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1195. CD70_2xCD3scFc_delGK bispecific HLE molecule evqllesggglvqpggslklscaasgftfs iyamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap r lliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy

-427043309

waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkp kdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqq gnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtImisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqpre pqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqqnvf scsvmhealhnhytqkslslspgk 1196. CD70_3_CCxC D3scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntIfIqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts

-428 043309

gnypnwvqqkpgqaprqliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvf1fppkpkdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcv svltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsgggqsggggsggggsggg gsggqgsdkth tcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsffly skitvdksrwqqqnvf scsvmhealhnhytqkslslspgk 1197. CD70_3xCD3scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntIfIqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprqliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv

-429043309

Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvslt clvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsgg gsggggsdkthtcppcpapelIggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktk pceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1198. CD70_4_CCxC D3scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkd tlmisrtpe

-430043309

vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsv mhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpape11ggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytl ppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1199. CD70_4xCD3scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkp kdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke

-431 043309

ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapelIggpsvf If ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnv f scsvmhealhnhytqkslslspgk 1200. CD70_5_CCxC Di- sc Fc_delGK bispecific HLE molecule evqllesggglvqsggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkl eiksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdtl misrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia

-432043309

vewesngqpennykttppvldsdgsfflys kltvdksrwgggnvfscsvmhealhnhytg kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceegygstyrc v svltvlhgdwlngkeykckvsnkalpapie ktiskakggprepgvytlppsreemtkngv sltclvkgfypsdiavewesnggpennykt tppvldsdgsfflyskitvdksrwgggnvf scsvmhealhnhytgkslslspgk 1201. CD70_5xCD3scFc_delGK bispecific HLE molecule evgllesggglvgsggslrlscaasgftfs syamswvrgapgkglewvsaisgsggrthy aesvkgrftisrdnskntlylgmnslraed tavyycakhdysnypyfdywgggtlvtvss ggggsggggsggggseivltgspgtlslsp geratlscrasgsvrssylawyggkpggap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycggygsspftfgpgtkl eiksggggsevglvesggglvgpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylgmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv уtlppsreemtkngvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytg

- 433 043309

kslslspggggsggggsggggsggggsgg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlnqkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtk nqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1202. CD70_6_CCxC D3scFc_delGK bispecific HLE molecule evqllesggglvqpggsIriscaasgftfs syamswvrqapgkclewvslisgsgqrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgqap rlliydassratgipdrfsgsgsgtdftit isrlepedfavyfcqygsspptfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqg tlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrt pe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsItclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvm healhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf

- 434 043309

ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgn vf scsvmhealhnhytqkslslspgk 1203. CD70_6xCD3scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvslisgsggrthy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgqap rlliydassratgipdrfsgsgsgtdftit isrlepedfavyfcqygsspptfgggtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgt lvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkitvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvm healhnhytq kslslspggggsgggqsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv

- 435 043309

svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1204. CD70_7_CCxC D3scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlslqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtIvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpk dtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnv fscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepq vytlppsreemtknqv

- 436 043309

sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1205. CD70_7xCD3scFc_delGK bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs tyamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntIsIqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkp gqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyis y waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfifppkp kdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgn vfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfif ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprep qvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf

- 437 043309

scsvmhealhnhytqkslslspgk 1206. CD70_8_CCxC D3scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs tyamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgcgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkd tlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnv fscsvmhealhnhytq kslslspggggsqgggsggggsgggqsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprep qvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1207. CD70_8xCD3- bispecifically evqllesgggmvqpggslrIscaasgftfs

- 438 043309

scFc_delGK cheskaya HLE molecule tyamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrstylawyqqkpgqap rlliygassratgipdrfsgsgsgtdft it isrlepedfavyscqqygdlpftfgpgtkl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvv tqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkpkdtImisrtpe vtcvvvdvshedpevkfnwyv dgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv уtlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsgg ggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewe sngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1208. CD70_9_CCxC D3scFc_delGK bispecifically cheskaya HLE evqllesggglvqpggsIriscaasgftfs syamswvrqapgkclewvsaisgsggytyy aesvkgrftisrdnskntlylqmnslraed

- 439 043309

molecule tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggs lkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflap gtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiek tiskakgqprepqv utIppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthteppepapellggpsvfIf ppkpkdtlmisrtpevtcvv vdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslsp gk 1209. CD70_9xCD3scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggytyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp

- 440 043309

geratlscrasqsvrsnylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta y 1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlgggg dkthtcpp cpapellggpsvfIfppkpkdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennyktt ppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtImisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqd wlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1210. CD70_10_CCx CD3scFc_delGK bispecific HLE molecule evqllesggglaqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyfcakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit

- 441 043309

isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tv vtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyv dgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv уtlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsgg ggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewe sngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1211. CD70_10xCD3 -scFc_delGK bispecific HLE molecule evqllesggglaqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggstfу aesvkgrftisrdnskntlylqmnslraed tavyfcakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls

- 442 043309

caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprqliggtkflap gtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlqgggdkthtcpp cpapellggpsvf1fppkpkdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpa piektiskakgqprepqv ytippsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspqgggsggggsgqggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtp evtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytq kslslspgk 1212. CD70_ll_CCx POP- sc Fc_delGK bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta

- 443 043309

ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvl ggggdkthtcpp cpapelIggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykt tppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapelIggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhq dwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1213. CD70_llxCD3 -scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq

-444043309

tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfn wyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytIppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsgg ggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfyps diavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk CD70_12_CCx bispecifically cheskaya evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit 1214. CD3scFc_delGK HLE molecule isrlepedfavyycqqygsspftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvt qepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp

-445 043309

arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkpkdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektis kakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsgggqsggggsggggsggg gsggqgsdkthtcppcpape11ggpsvfIf ppkpkdtlmisrtpev tcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytq kslslspgk 1215. CD70_12xCD3 -scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp

-446043309

cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv уtlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgs fflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckv snkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1216. CD70_13_CCx CD3scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggstfу aesvqgrftisrdnskntlylqvnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrgnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta uIqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdt lmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak

-447043309

tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv уtlppsreemtknqvsItclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggs ggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennyk t tppvidsdgsfflyskitvdksrwqqqnvf scsvmhealhnhytqkslslspgk 1217. CD70_13xCD3 -scFc_delGK bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggstfу aesvqgrftisrdnskntlylqvnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrgnylawyqqkp gqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygyspftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkd tlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv

-448 043309

уtlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapelIggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedp ev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1218. CD70_14_CCx POP- sc Fc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkclewvsaisgsgggtfu aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygsspftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdt lmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys

-449043309

kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsqgggsggggsgggqsggq gsgqggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckv snkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1219. CD70_14xCD3 -scFc_delGK bispecific HLE molecule evqllesggglvqpggslriscaasgftfs tyamswvrqapgkglewvsaisgsgggtfu aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpgq ap rlliygassratqipdrfsgsgsgtdftit isrlepedfavyуcqqygsspftfgpgtkv eiksggggsevqlvesqgglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfifppkpkdtl misrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscs vmhealhnhytq kslslspggggsqgggsggggsgggqsggq

- 450 043309

gsggggsdkthtcppcpape11ggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpenny kt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1220. CD70_15_CCx CD3scFc_delGK bispecific HLE molecule evqllesggglvqpggsIrIscaasgftfs tyamswvrqapgkclewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpg qap rlliygasnratgipdrfsgsgsgtdftit isrlepedfavyscqqygispptfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywg qgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkpkdt Imisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfsc svmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpape11ggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev

- 451 043309

kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1221. CD70_15xCD3 -scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygasnratgipdrfsgsgsgtdftit isrlepedfavyscqqygispptfgggtkv eiksggqgsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqg tlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrt pe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsv mhealhnhytq kslslspggggsgggqsggggsggggsggq gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie

- 452 043309

ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1222. CD70_16_CCx CD3scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqspgkclewvsaisgsggraqy aesvqgrftvsrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspatlsvsp geratlscrasqsvssnlawyqqkpg qapr 1liygsssratgipdrfsgsgsgtdftlti srlepedfavyycqqygsspppfgcgtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgnsyis yw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfIfppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tIppsreemtknqvsltclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk 1tvdksrwqqgnvfscsvmhealhnhytqk slslspggggsggggsggggsggggsgggg sggggsdkthtcppcpapellggpsvfIfp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpce eqygstyrcvs vltvlhqdwlngkeykckvsnkalpapiek tiskakgqprepqvytlppsreemtknqvs 1tclvkgfypsdiavewesngqpennyktt

- 453 043309

ppvldsdgsfflyskltvdksrwqqgnvfs csvmhealhnhytqkslslspgk 1223. CD70_16xCD3 -scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqspgkglewvsaisgsggraqy aesvqgrftvsrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspatlsvsp geratlscrasqsvssnlawyqqkpg qapr lliygsssratgipdrfsgsgsgtdftlti srlepedfavyycqqygsspppfgggtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay 1qmnnlktedtavyycvrhgnfgnsyisy w aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfIfppkpkdtImisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspggggsggggsggggsggggsgggg sggggsdkthtcppcpapellggpsvfIfp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpceeq ygstyrcvs vltvlhqdwlngkeykckvsnkalpapiek tiskakgqprepqvytlppsreemtknqvs Itclvkgfypsdiavewesngqpennyktt ppvldsdgsfflyskltvdksrwqqgnvfs csvmhealhnhytqkslslspgk

- 454 043309

1224. CD70_17_CCx CD3scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrsdylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyhcqqygstpptfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkpk dtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgn vfscsvmhealhnhytq kslslspggggsgggqsggggsggggsggg gsggggsdkthtcppcpape11ggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgq prepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1225. CD70_17xCD3 -scFc_delGK bispecifically cheskaya evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу

- 455 043309

HLE molecule aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrsdylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyhcqqygstpptfgggtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypn wvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhq dwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellgg psvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrwq qgnvf scsvmhealhnhytqkslslspgk 1226. CD70_18_CCx CD3scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkclewvsaigegggytyy aesvkgrftisrdnskntlsllmnslraed tavyycarhdysnypyfdywgqgtlvtvss

- 456 043309

ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssyfawyqqkpgqap rlliygastratgiparfsgsgsgtdftit isrlepedfavyycqqygsspptfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyad Iwysn rwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv уtlppsreemtknqvsltclvkgfyps dia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapelIggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygs tyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1227. CD70_18xCD3 -scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs syamswvrqapgkglewvsaigegggytyy aesvkgrftisrdnskntlsllmnslraed tavyycarhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssyfawyqqkpgqap

- 457 043309

rlliygastratgiparfsgsgsgtdftit isrlepedfavyycqqygsspptfgqgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvt vt cvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmheal hnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreem tknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1228. CD70_19_CCx CD3scFc_delGK bispecific HLE molecule evqllesgggvvqpgrsirIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygssppsfgcgtkv

- 458 043309

eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnyp nwvqqkpgqaprqliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvf1fppkpkdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltv lhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsgggqsggggsggggsggg gsggggsdkthtcppc papellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvd ksrwqqgnvf scsvmhealhnhytqkslslspgk 1229. CD70_19xCD3 -scFc_delGK bispecifically cheskaya HLE molecule evqllesgggvvqpgrslrIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsirsnylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygssppsfgqgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari

- 459 043309

rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaey ycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqv sltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnak tkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1230. CD70_20_CCx CD3scFc_delGK bispecific HLE molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkclewvsaisgsgggtfu aesvegrftisrdnskntlylqmnslraed tavyycarhdysnypyfdywglgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy

-460043309

waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkp kdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqq gnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapelIggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqpre pqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1231. CD70_20xCD3 -scFc_delGK bispecific HLE molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkglewvsaisgsgggtfu aesvegrftisrdnskntlylqmnslraed tavyycarhdysnypyfdywglgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyscqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts

-461 043309

gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsv ltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv уtlppsreemtknqvsItclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppc papellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvidsdgsfflyskitvdks rwqqqnvf scsvmhealhnhytqkslslspgk 1232. CD70_21_CCx CD3scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrIscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv

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Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvslt clvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsgg gsggggsdkthtcppcpapelIggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktk pceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1233. CD70_21xCD3 -scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyyctkhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy wayw gqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapelIggpsvfIfppkpkdt lmisrtpe

-463 043309

vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtkngvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwgggnvfscsvmheal hnhytg kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceegygstyrcv svltvlhgdwlngkeykckvsnkalpapie ktiskakggprepgvytlppsreemt kngv sltclvkgfypsdiavewesnggpennykt tppvldsdgsfflyskitvdksrwgggnvf scsvmhealhnhytgkslslspgk 1234. CD70_22_CCx CD3scFc_delGK bispecific HLE molecule evgllesggglvgpggslrlscaasgftfs tyamswvrgapgkclewvslisgsggrtyy aesvkgrftisrdnskntlylgmnslraed tavyycakhdysnypyfdywgggtlvtvss ggggsggggsggggseivltgspgtlslsp geratlscrasqgvrssylawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycgqygsspptfgcgtkv diksggggsevqlvesggglvqpggsIkis caasgftfnkyamnwvrgapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylgmnnlktedtavyycvrhgnfgnsyisy waywggg tlvtvssggggsggggsggggsg tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvgpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrt pe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceegygstyrcvsvltvlhgdwlngke

-464043309

ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvf If ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqq nvf scsvmhealhnhytqkslslspgk 1235. CD70_22xCD3 -scFc_delGK bispecific HLE molecule evqllesggglvqpggslrlscaasgftfs tyamswvrqapgkglewvslisgsggrtyy aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqgvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgggtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqg tlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkitvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrt pe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia

-465 043309

vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygs tyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1236. CD70_23_CCx CD3scFc_delGK bispecific HLE molecule evqllesgggvvqpgrslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgcgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmis rtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsv mhealhnhytq

- 466 043309

kslslspggggsggggsggggsggggsgg gsggggsdkthtcppcpape11ggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtk nqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1237. CD70_23xCD3 -scFc_delGK bispecific HLE molecule evqllesgggvvqpgrsirIscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrsnylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit inrlepedfavyycqqygsspptfgggtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqg tlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkpkdtImis rtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsv mhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpape11ggpsvfIf

- 467 043309

ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgn vf scsvmhealhnhytqkslslspgk 1238. CD70_24_CCx CD3scFc_delGK bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkclewvsvisgsggitdf aesvkgrftisrdnsrntlylqmnslraed tavyfcarhdysnyfffdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqqisnylawyqqk pqkvpk lliyaasilqsgvpskfsgsgsgtdftlti sslqpedfaiyycqqyfaypitfgcgtrle iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgn syisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvlggggdkthtcppc pape11ggpsvfIfppkpkdtImisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkg fypsdiav ewesngqpennykttppvldsdgsfflysk 1tvdksrwqqgnvfscsvmhealhnhytqk slslspggggsggggsggggsggggsgggg sggggsdkthtcppcpape11ggpsvfifp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktk pceeqygstyrcvs

- 468 043309

vltvlhqdwlngkeykckvsnkalpapiek tiskakgqprepqvytlppsreemtknqvs itclvkgfypsdiavewesngqpennyktt ppvldsdgsfflyskitvdksrwqqgnvfs csvmhealhnhytqkslslspgk 1239. CD70_24xCD3 -scFc_delGK bispecific HLE molecule evqllesggglvqpggslrIscaasgftfs syamswvrqapgkglewvsvisgsggitdf aesvkgrftisrdnsrntlylqmnslraed tavyfcarhdysnyfffdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyqqk pgkvpk lliyaasilqsgvpskfsgsgsgtdftlti sslqpedfaiyycqqyfaypitfgqgtrle iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgn syisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspqgtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycvl wysnrwvfgggtkltvlggggdkthtcppc papellggpsv fifppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgfypsdiav ewesngqpennykttppvldsdgsfflysk itvdksrwqq gnvfscsvmhealhnhytqk slslspggggsggggsggggsggggsgggg sggggsdkthtcppcpapellggpsvfifp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpceeqygstyrcvs vltvlhqdwlngkeykckvsnkalpapiek tiskakgq prepqvytlppsreemtknqvs

- 469 043309

1tclvkgfypsdiavewesngqpennyktt ppvldsdgsfflyskitvdksrwqqqnvfs csvmhealhnhytqkslslspgk 1240. CD70_25_CCx CD3scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkclewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgcgtrl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgq gtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmis rtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscs vmhealhnhytq kslslspggggsqgggsggggsgggqsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvyt lppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf

- 470 043309

scsvmhealhnhytqkslslspgk 1241. CD70_25xCD3 -scFc_delGK bispecific HLE molecule evqllesgggmvqpggslrlscaasgftfs syamswvrqapgkglewvsaisgsggrtfу aesvegrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpgq ap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyfcqqygsspptfgggtrl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqg tlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrt pe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utIppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvm healhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlpps reemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1242. CD70_26_CCx bispecifically evqllesggglvqpggslrlscaasgftfs

- 471 043309

CD3scFc_delGK cheskaya HLE molecule iyamswvrqapgkclewvsaiggsggstfу aesvkgrftisrdnskntlylqmnslraed tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssyvawyqqkpgqap rlliygassratgipdrfsgsgsgtd ftit isrlepedfavyycqqygdlpftfgcgtrl eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tv vtqepsltvspggtvtltcgsstqavts gnypnwvqqkpgqaprqliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvf1fppkpkdtImisrtpe vtcvvvdvshedpevkfnw yvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsgg ggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfyps diavewesngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1243. CD70_26xCD3 -scFc_delGK bispecifically cheskaya HLE evqllesggglvqpggslrIscaasgftfs iyamswvrqapgkglewvsaiggsggstfу aesvkgrftisrdnskntlylqmnslraed

- 472 043309

molecule tavyycakhdysnypyfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssyvawyqqkpgqap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtrl eiksggggsevqlvesggglvqpggs lkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta u1qmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflap gtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiek tiskakgqprepqv уtlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtc vvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqksls lspgk 1244. CD70_27_CCx POP- sc Fc_delGK bispecific HLE molecule qvqlqesgpglvkpsqtlsltctvsggsis sssyywgwirqppgkclewigsiyhsggty fnpslksrvtisvdtsknqfslklssvtaa dtavyycarhyeiltgyypdvfdiwgqgtm vtvssggggsggggsggggsdiqmtqspss

- 473 043309

Isasvgdrvtitcrasqsissylnwyqqkp gkapklliyaasnlqsgvssrfsgsgsgtd ftltisslqpedfatyycqqsfssprtfgc gtkveiksggggsevqlvesggglvqpggs Ikiscaasgftfnkyamnwvrqapgkglew varirskynnyatyyadsvkdr ftisrdds kntaylqmnnlktedtavyycvrhgnfgns yisywaywgqgtlvtvssggggsggggsgg ggsqtvvtqepsltvspggtvtltcgsstg avtsgnypnwvqqkpgqaprgliggtkf!a pgtparfsgsllggkaaltlsgvqpedeae yycvlwys nrwvfgggtkltvlggggdkth tcppcpapellggpsvfIfppkpkdtImis rtpevtcvvvdvshedpevkfnwyvdgvev hnaktkpceeqygstyrcvsvltvlhqdwl ngkeykckvsnkalpapiektiskakgqpr epqvytlppsreemtknqvsItclvkgf yp sdiavewesngqpennykttppvldsdgsf flyskltvdksrwqqgnvfscsvmhealhn hytqkslslspggggsggggsggggsgggg sggggsggggsdkthtcppcpapellggps vfIfppkpkdtImisrtpevtcvvvdvshe dpevkfnwyvdgvevhnaktkpcee qygst yrcvsvltvlhqdwlngkeykckvsnkalp apiektiskakgqprepqvytlppsreemt knqvsItclvkgfypsdiavewesngqpen nykttppvldsdgsfflyskitvdksrwqq gnvfscsvmhealhnhytqkslslspgk 1245. CD70_27xCD3 -scFc_delGK bispecific HLE molecule qvqlqesgpglvkpsqtlsltctvsggsis sssyywgwirqppgkglewigsiyhsggty fnpslksrvtisvdtsknqfslklssvtaa dtavyycarhyeiltgyypdvfdiwgqgtm vtvssggggsggggsggggsdiqmtqspss Isasvgdrvtitcrasqsis sylnwyqqkp gkapklliyaasnlqsgvssrfsgsgsgtd

- 474 043309

ftltisslqpedfatyycqqsfssprtfgq gtkveiksggggsevqlvesggglvqpggs 1klscaasgftfnkyamnwvrqapgkglew varirskynnyatyyadsvkdrftisrdds kntaylqmnnlktedtavyycvrhgnfgns yisywaywgqgtlvtvssggggsgggg sgg ggsqtvvtqepsltvspggtvtltcgsstg avtsgnypnwvqqkpgqaprgliggtkf!a pgtparfsgsllggkaaltlsgvqpedeae yycvlwysnrwvfgggtkltvlggggdkth teppepapellggpsvfIfppkpkdtlmis rtpevtcvvv dvshedpevkfnwyvdgvev hnaktkpceeqygstyrcvsvltvlhqdwl ngkeykckvsnkalpapiektiskakgqpr epqvytIppsreemtknqvsltclvkgfyp sdiavewesngqpennykttppvldsdgsf flyskltvdksrwqqgnvfscsvmhealhn hytq kslslspggggsggggsggggsgggg sggggsggggsdkthteppepapellggps vfIfppkpkdtlmisrtpevtcvvvdvshe dpevkfnwyvdgvevhnaktkpceeqygst yrcvsvltvlhqdwlngkeykckvsnkalp apiektiskakgqprepqvytlppsreemt knq vsltclvkgfypsdiavewesngqpen nykttppvldsdgsfflyskitvdksrwqq gnvfscsvmhealhnhytqkslslspgk 1246. CD70_28_CCx CD3scFc_delGK bispecific HLE molecule evqlvesggglvkpggslrlscaasgftfs sysmnwvrqapgkclewvsyisssggyiyy aesvkgrftisrdnaknslylqmnslraed aavyycsrgdysnyayfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyq qkpgkvpk lliyaastlqsgvpsrfsgsgsgtdftlti sslqaedvavyycqqyystpltfgcgtkve iksggggsevqlvesggglvqpggslklsc

- 475 043309

aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkfla pgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvlggggdkthtcppc papelIggpsvfIfppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspggggsggggsggggsggggsgggg sggggsdkthtcppcpapellggpsvfIfp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpceeq ygstyrcvs vltvlhqdwlngkeykckvsnkalpapiek tiskakgqprepqvytlppsreemtknqvs 1tclvkgfypsdiavewesngqpennyktt ppvldsdgsfflyskitvdksrwqqgnvfs csvmhealhnhytqkslslspgk 1247. CD70_28xCD3 -scFc_delGK bispecific HLE molecule evqlvesggglvkpggslrlscaasgftfs sysmnwvrqapgkglewvsyisssggyiyy aesvkgrftisrdnaknslylqmnslraed aavyycsrgdysnyayfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtitcrasqgisnylawyq qkpgkvpk lliyaastlqsgvpsrfsgsgsgtdftlti sslqaedvavyycqqyystpltfgggtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay

- 476 043309

Iqmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfIfppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tIppsreemtknqvsItclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspggggsggggsggggsggggsgggg sggggsdkthtcppcpapellggpsvfIfp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpceeq ygstyrcvs vltvlhqdwlngkeykckvsnkalpapiek tiskakgqprepqvytlppsreemtknqvs 1tclvkgfypsdiavewesngqpennyktt ppvldsdgsfflyskitvdksrwqqgnvfs csvmhealhnhytqkslslspgk CD70_29_CCx bispecifically cheskaya evqllesggglvqpggslrIscaasgftfs vyamswvrqapgkclewvstisgsggstfу aesvkgrftisrdnskntlylqmnrlraed tavyycarhdysnyayfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap 1248. CD3scFc_delGK HLE molecule rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgcgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy way wgqgtlvtvssggggsggggsggggsq

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tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfppkpkdtImisrtpe vtcvvvdvshedpevkf nwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv utlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggs ggggsggggsggggsggg gsggggsdkthtcppcpape11ggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sltclvkgf ypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1249. CD70_29xCD3 -scFc_delGK bispecific HLE molecule evqllesggglvqpggsIrIscaasgftfs vyamswvrqapgkglewvstisgsggstfу aesvkgrftisrdnskntlylqmnrlraed tavyуcarhdysnyayfdywgqgtlvtvss ggggsggggsggggseivltqspgtlslsp geratlscrasqsvrssylawyqqkpg qap rlliygassratgipdrfsgsgsgtdftit isrlepedfavyycqqygdlpftfgpgtkv eiksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsyisy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp

-478 043309

arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppkpkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiska kgqprepqv уtlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwqqgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvv vdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktiskakgqprepqvytlppsreemtknqv sitclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqkslslspg k 1250. CD70_30_CCx CD3scFc_delGK bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgfmfs sygmhwvrqapgkclewvavisyegsnkyy aesvkgrftisrdnskntlylqmnslraed tavyycargryygsgnynhgmdvwgqgttv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqsis sylnwyqqkpg kapklliyaasslqsgvpsrfsgrgsgtdf tltisslqpedfatyycqqsystpftfgcg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntayIqmnnlktedtavyy cvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht

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cppcpapelIggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsd gsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeyk ckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 1251. CD70_30xCD3 -scFc_delGK bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgfmfs sygmhwvrqapgkglewvavisyegsnkyy aesvkgrftisrdnskntlylqmnslraed tavyycargryygsgnynhgmdvwgqgttv tvssggggsggggsggggsdiqmtqspssl sasvgdrvtitcrasqsis sylnwyqqkpg kapklliyaasslqsgvpsrfsgrgsgtdf tltisslqpedfatyуcqqsystpftfgpg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyyc vrhgnfgnsy isywaywgqgtlvtvssggggsggggsgg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelI ggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh

-480043309

naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpen n ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk CD70_31_CCx bispecifically cheskaya qvqlvesgggvvqpgrsirIscaasgftfs sygmhwvrqapgkclewvavtwydasnkyy gdavkgrftisrdnskntlylqmnslraed tavyycardllrgvkqyamdvwgqgttvtv ssggqgsggggsgggqseivltqspgtlsl spgeratlscrasqslrriylaw yqqkpgq aprlliydvfdratgipdrfsgggsgtdft Itisrlepedfavyycqqysespftfqcgt kvdiksggggsevqlvesggglvqpgqslk Iscaasgftfnkyamnwvrqapgkglewva 1252. CD3scFc_delGK HLE molecule rirskynnyatyyadsvkdrftisrddskn tay1qmnnlktedtavyycvrhgnfgnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedea eyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpapellggpsvfIfppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep

-481 043309

qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsff1 yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspggggsggggsggggsggggsg gggsggggsdkthtcppcpapelIggpsvf Ifppkpkdtlmisrtpevtcvvvd vshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckvsnkalpap iektiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslsl spgk 1253. CD70_31xCD3 -scFc_delGK bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgftfs sygmhwvrqapgkglewvavtwydasnkyy gdavkgrftisrdnskntlylqmnslraed tavyycardllrgvkgyamdvwgqgttvtv ssggggsggggsggggseivltqspgtlsl spgeratlscrasqslrriylawyq qkpgq aprlliydvfdratgipdrfsgggsgtdft Itisrlepedfavyycqqysespftfgpgt kvdiksggggsevqlvesggglvqpggsIk Iscaasgftfnkyamnwvrqapgkglewva rirskynnyatyyadsvkdrftisrddskn taylqmnnlktedtavyycvrhgnf gnsyi sywaywgqgtlvtvssggggsggggsgggg sqtvvtqepsltvspggtvtltcgsstgav tsgnypnwvqqkpgqaprgliggtkflapg tparfsgsllggkaaltlsgvqpedeaeyy cvlwysnrwvfgggtkltvlggggdkthtc ppcpapelIggpsvfIf ppkpkdtlmisrt pevtcvvvdvshedpevkfnwyvdgvevhn aktkpceeqygstyrcvsvltvlhqdwlng keykckvsnkalpapiektiskakgqprep qvytlppsreemtknqvsltclvkgfypsd iavewesngqpennykttppvldsdgsffl

-482043309

yskltvdksrwqqgnvfscsvmhealhnhy tqkslslspggggsggggsggggsggggsg gggsggggsdkthtcppcpapellggpsvf Ifppkpkdtlmisrtpevtcvvvdvshedp evkfnwyvdgvevhnaktkpceeqygstyr cvsvltvlhqdwlngkeykckv snkalpap iektiskakgqprepqvytlppsreemtkn qvsItclvkgfypsdiavewesngqpenny kttppvldsdgsfflyskitvdksrwqqgn vfscsvmhealhnhytqkslslspgk 1254. CD70_32_CCx CD3scFc_delGK bispecific HLE molecule qvqlvqsgaevkkpgasvkvsckasgytft sygiswvrqapgqclewmgwisayqgythy aqklqgrvtmttdtststaymelrslrsdd tavyycardyggndyygmdvwgqgttvtvs sggggsggggsggggsqsvltqppsasgtp gqrvtiscsgsssnigin yvywyqqlpgta pklliyrsdqrpsgvpdrfsgsksgtsasl alsglrsedeadyycaafdesIsgvvfgcg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedta vyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppc papellggpsvf1fppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs

- 483 043309

ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsItclvkgfypsdiavewesngq penn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 1255. CD70_32xCD3 -scFc_delGK bispecific HLE molecule qvqlvqsgaevkkpgasvkvsckasgytft sygiswvrqapgqglewmgwisayqgythy aqklqgrvtmttdtststaymelrslrsdd tavyycardyggndyygmdvwgqgttvtvs sggggsggggsggggsqsvltqppsasgtp gqrvtiscsgsssnigin yvywyqqlpgta pklliyrsdqrpsgvpdrfsgsksgtsasl alsglrsedeadyycaafdeslsgvvfggg tkltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntayIqmnnlktedtavy ycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcp apellggpsvf1fppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff ly skltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed

- 484 043309

pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslsl spgk 1256. CD70_33_CCx POP- sc Fc_delGK bispecific HLE molecule qaqlvesgggvvqpgrsirIscaasgftfs yygmhwvrqapgkclewvaviwydasnkyy adavkgrftisrdnskntlylqmnslraed tavyycardremgsrgdfdywgqgtlvtvs sggggsggggsggggsdiqmtqspsslsas vgdrvtitcrasqginnylawfq qkpgkap ksliyavsilqsgvpskfsgsgsgtdftit isnlqpedfatyycqqynfypfsfgcgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsy isy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpapellggpsvfIfppk pkdtlmisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrwq qgnvfscsvmhealhnhytq kslslspggggsggggsggggsggggsggg gsggggsdkthtcppcpapellggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie

- 485 043309

ktiskakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1257. CD70_33xCD3 -scFc_delGK bispecific HLE molecule qaqlvesgggvvqpgrsirIscaasgftfs yygmhwvrqapgkglewvaviwydasnkyy adavkgrftisrdnskntlylqmnslraed tavyycardremgsrqdfdywgqgtlvtvs sggggsggggsggggsdiqmtqspsslsas vgdrvtitcrasqginnylawfq qkpgkap ksliyavsilqsgvpskfsgsgsgtdftit isnlqpedfatyycqqynfypfsfgqgtkv diksggggsevqlvesggglvqpggslkls caasgftfnkyamnwvrqapgkglewvari rskynnyatyyadsvkdrftisrddsknta ylqmnnlktedtavyycvrhgnfgnsy isy waywgqgtlvtvssggggsggggsggggsq tvvtqepsltvspggtvtltcgsstgavts gnypnwvqqkpgqaprgliggtkflapgtp arfsgsllggkaaltlsgvqpedeaeyycv Iwysnrwvfgggtkltvlggggdkthtcpp cpape11ggpsvfIfpp kpkdtImisrtpe vtcvvvdvshedpevkfnwyvdgvevhnak tkpceeqygstyrcvsvltvlhqdwlngke ykckvsnkalpapiektiskakgqprepqv ytlppsreemtknqvsltclvkgfypsdia vewesngqpennykttppvldsdgsfflys kltvdksrw qqgnvfscsvmhealhnhytq kslslspggggsgggqsggggsggggsggg gsggggsdkthtcppcpape11ggpsvfIf ppkpkdtlmisrtpevtcvvvdvshedpev kfnwyvdgvevhnaktkpceeqygstyrcv svltvlhqdwlngkeykckvsnkalpapie ktis kakgqprepqvytlppsreemtknqv sltclvkgfypsdiavewesngqpennykt

- 486 043309

tppvldsdgsfflyskitvdksrwqqgnvf scsvmhealhnhytqkslslspgk 1258. CD70_34_CCx CD3scFc_delGK bispecifically cheskaya HLE molecule qvqlqqwgagllkpsetlsltcavyggsfs gfywswirqppgkclew!gelyhsghatnn pslksrvtisldtsknqfslklnsvtaadt avyycarggnsgyifdywgqgtlvtvssgg ggsggggsggggsdvqmtqspsslsasvgd rvtitcrtsqyigrylnwy qqkpgkapkvl iygastlqqgvpsrfsgsgsgtdftltits Iqpedfasyycqqtystprtfgcgtkveik sggggsevqlvesggglvqpggsIkiscaa sgftfnkyamnwvrqapgkglewvarirsk ynnyatyyadsvkdrftisrddskntaylq mnnlktedtavyycv rhgnfgnsyisyway wgqgtlvtvssggggsggggsggggsqtvv tqepsltvspggtvtltcgsstgavtsgny pnwvqqkpgqaprgliggtkflapgtparf sgsllggkaaltlsgvqpedeaeyycvlwy snrwvfgggtkitvlggggdkthtcppcpa pellggpsv fIfppkpkdtlmisrtpevtc vvvdvshedpevkfnwyvdgvevhnaktkp ceeqygstyrcvsvltvlhqdwlngkeykc kvsnkalpapiektiskakgqprepqvytl ppsreemtknqvsltclvkgfypsdiavew esngqpennykttppvldsdgsfflyskit vdksrwq qgnvfscsvmhealhnhytqksl slspggggsggggsggggsggggsggggsg gggsdkthtcppcpapellggpsvfIfppk pkdtlmisrtpevtcvvvdvshedpevkfn wyvdgvevhnaktkpceeqygstyrcvsvl tvlhqdwlngkeykckvsnkalpapiekti skakg qprepqvytlppsreemtknqvslt clvkgfypsdiavewesngqpennykttpp vldsdgsfflyskitvdksrwqqgnvfscs vmhealhnhytqkslslspgk

- 487 043309

1259. CD70_34xCD3 -scFc_delGK bispecific HLE molecule qvqlqqwgagllkpsetlsltcavyggsfs gfywswirqppgkglewigeiyhsghatnn pslksrvtisldtsknqfslklnsvtaadt avyуcarggnsgyifdywgqgtlvtvssgg ggsggggsggggsdvqmtqspsslsasvgd rvtitcrtsqyigrylnwyq qkpgkapkvl iygastlqqgvpsrfsgsgsgtdftltits Iqpedfasyycqqtуstprtfgggtkveik sggggsevqlvesggglvqpggsIkiscaa sgftfnkyamnwvrqapgkglewvarirsk ynnyatyyadsvkdrftisrddskntaylq mnnlktedtavyycvr hgnfgnsyisyway wgqgtlvtvssggggsggggsggggsqtvv tqepsltvspggtvtltcgsstgavtsgny pnwvqqkpgqaprgliggtkflapgtparf sgsllggkaaltlsgvqpedeaeyycvlwy snrwvfgggtkltvlggggdkthtcppcpa pellggpsvf 1fppkpkdtImisrtpevtc vvvdvshedpevkfnwyvdgvevhnaktkp ceeqygstyrcvsvltvlhqdwlngkeykc kvsnkalpapiektiskakgqprepqvytl ppsreemtknqvsltclvkgfypsdiavew esngqpennykttppvldsdgsfflyskit vdksrwq qgnvfscsvmhealhnhytqksl slspggggsggggsggggsggggsggggsg gggsdkthtcppcpapellggpsvfIfppk pkdtlmisrtpevtcvvvdvshedpevkfn wyvdgvevhnaktkpceeqygstyrcvsvl tvlhqdwlngkeykckvsnkalpapiekti skakg qprepqvytlppsreemtknqvslt clvkgfypsdiavewesngqpennykttpp vldsdgsfflyskltvdksrwqqgnvfscs vmhealhnhytqkslslspgk 1260. CD70_35_CCx CD3- bispecifically cheskaya qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkclewvaviwyegsnkyy

- 488 043309

scFc_delGK HLE molecule gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgttvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagydvnwyqqfpgta pklliyvnnnrpsgvpdrfsgstsgtsasl aitglqaedeady ycqsydtslsasvfgeg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntayIqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepslt vspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpape11ggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 1261. CD70_35xCD3 -scFc_delGK bispecific HLE molecule qvqlvesgggvvqpgrsirIscaasgftfs tygmhwvrqapgkglewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgttvtvss

- 489 043309

ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagydvnwyqqfpgta pklliyvnnnnrpsgvpdrfsgstsgtsasl aitglqaedeadyycqsydtslsasvfggg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnw vrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaal tlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapelIggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytl ppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfn wyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvs1tclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 1262. CD70_36_CCx POP- sc Fc_delGK bispecifically cheskaya HLE molecule qvqlvesgggvvqpgrslrlscaasgftfs tygmhwvrqapgkclewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgtlvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagyd vnwyqqlpgta

- 490 043309

pklliyvnnnrpsgvpdrfsgsksgtsasl aitglqaedeadyycqsyetslsasvfgeg trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy is ywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkp kdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvsvltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsltclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnv fscsvmhealhnh ytqkslslspggggsggggsggggsggggs ggggsggggsdkthtcppcpapellggpsv fIfppkpkdtlmisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqpre pqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgsfflyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 1263. CD70_36xCD3 -scFc_delGK bispecific HLE molecule qvqlvesgggvvqpgrslrlscaasgftfs tygmhwvrqapgkglewvaviwyegsnkyy gesvkgrftisrdnskntlylqmnslraed tavyycardnshyyygmdvwgqgtlvtvss ggggsggggsggggsqsvltqppsvsgapg qrvtisctgsssnigagyd vnwyqqlpgta pklliyvnnnrpsgvpdrfsgsksgtsasl aitglqaedeadyycqsyetslslasvfggg

- 491 043309

trltvlsggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlktedtavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vt sgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvlggggdktht cppcpapellggpsvfIfppkpkdtlmisr tpevtcvvvdvshedpevkfnwyvdgvevh naktkpceeqygstyrcvs vltvlhqdwln gkeykckvsnkalpapiektiskakgqpre pqvytlppsreemtknqvsItclvkgfyps diavewesngqpennykttppvldsdgsff lyskltvdksrwqqgnvfscsvmhealhnh ytqkslslspggggsgggqsggggsggggs ggggsggggsdkthtcppc papellggpsv fIfppkpkdtImisrtpevtcvvvdvshed pevkfnwyvdgvevhnaktkpceeqygsty rcvsvltvlhqdwlngkeykckvsnkalpa piektiskakgqprepqvytlppsreemtk nqvsltclvkgfypsdiavewesngqpenn ykttppvldsdgs ff lyskitvdksrwqqg nvfscsvmhealhnhytqkslslspgk 1264. CD70_37_CCx CD3scFc_delGK bispecific HLE molecule qmqlqesgpglvkpsetlsltctvsggsie sgvyywswirqppgkclewigyiyysgsts ynpslksrltmsvdtsknqfslklssvtaa dtavyycarsgysyalfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasl gdrvtitcrasqsvdry fnwyqqkpgkapk vlifaasslqsgvpsrfsgsgsgtdftit1 sslqpedfatyycqqsystpwtfgcgtkve vksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir

- 492 043309

skynnyatyyadsvkdrftisrddskntay 1qmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedea eyycv! wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfIfppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tIppsreemtknqvsltclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspggggsggggsggggsggggsgggg sggggsdkthtcppcpapellggpsvfIfp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpceeq ygstyrcvs vltvlhqdwlngkeykckvsnkalpapiek tiskakgqprepqvytlppsreemtknqvs Itclvkgfypsdiavewesngqpennyktt ppvldsdgsfflyskitvdksrwqqgnvfs csvmhealhnhytqkslslspgk 1265. CD70_37xCD3 -scFc_delGK bispecific HLE molecule qmqlqesgpglvkpsetlsltctvsggsie sgvyywswirqppgkglewigyiyysgsts ynpslksrltmsvdtsknqfslklssvtaa dtavyycarsgysyalfdywgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasl gdrvtitcrasqsvdry fnwyqqkpgkapk vlifaasslqsgvpsrfsgsgsgtdftlti sslqpedfatyycqqsystpwtfgqgtkve vksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay 1qmnnlktedtavyy cvrhgnfgnsyisyw

-493 043309

aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprqliggtkflapqtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfIfppkpkdtImisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsItclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspggggsggggsggggsggggsgggg sggggsdkthtcppcpapellggpsvfIfp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpceeq ygstyrcvs vltvlhqdwlngkeykckvsnkalpapiek tiskakgqprepqvytlppsreemtknqvs Itclvkgfypsdiavewesngqpennyktt ppvldsdgsfflyskltvdksrwqqgnvfs csvmhealhnhytqkslslspgk 1266. CD70_38_CCx CD3scFc_delGK bispecific HLE molecule qvqlqesgpglvkpsqtlsltctvsgdsii sggyywswirqppgkclewigyifysgstd ynpslksrvtisvdtsknqfslklssvtaa dtavyycarsgysyalfdawgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtiscrasqfigryfnwy qqkpgkapk vliyaesslqsgvpsrfsgsgsgteftlti sslqpedfatyycqqsystpwtfgcgtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay 1qmnnlktedtavyycvr hgnfgnsyisyw aywgqgtlvtvssggggsggggsggggsqt vvtqepsltvspggtvtltcgsstgavtsg

-494043309

nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv! wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfIfppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tlppsreemtknqvsltclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk 1tvdksrwqqgnvfscsvmhealhnhytqk slslspggggsggggsggggsggggsgggg sggggsdkthtcppcpapellggpsvfIfp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpce eqygstyrcvs vltvlhqdwlngkeykckvsnkalpapiek tiskakgqprepqvytlppsreemtknqvs 1tclvkgfypsdiavewesngqpennyktt ppvldsdgsfflyskitvdksrwqqgnvfs csvmheaIhnhytqkslslspgk 1267. CD70_38xCD3 -scFc_delGK bispecific HLE molecule qvqlqesgpglvkpsqtlsltctvsgdsii sggyywswirqppgkglewigyifysgstd ynpslksrvtisvdtsknqfslklssvtaa dtavyycarsgysyalfdawgqgtlvtvss ggggsggggsggggsdiqmtqspsslsasv gdrvtiscrasqfigryfnwy qqkpgkapk vliyaesslqsgvpsrfsgsgsgteftit! sslqpedfatyycqqsystpwtfgqgtkve iksggggsevqlvesggglvqpggslklsc aasgftfnkyamnwvrqapgkglewvarir skynnyatyyadsvkdrftisrddskntay Iqmnnlktedtavyycvrhgnfgnsyisyw aywgqgtlvtvssggggsggggsggggs qt vvtqepsltvspggtvtltcgsstgavtsg nypnwvqqkpgqaprgliggtkflapgtpa rfsgsllggkaaltlsgvqpedeaeyycv!

-495 043309

wysnrwvfgggtkltvlggggdkthtcppc papellggpsvfIfppkpkdtlmisrtpev tcvvvdvshedpevkfnwyvdgvevhnakt kpceeqygstyrcvsvltvlhqdwlngkey kckvsnkalpapiektiskakgqprepqvy tIppsreemtknqvsltclvkgf ypsdiav ewesngqpennykttppvldsdgsfflysk Itvdksrwqqgnvfscsvmhealhnhytqk slslspggggsggggsggggsggggsgggg sggggsdkthteppepapellggpsvfIfp pkpkdtlmisrtpevtcvvvdvshedpevk fnwyvdgvevhnaktkpceeqygs tyrcvs vltvlhqdwlngkeykckvsnkalpapiek tiskakgqprepqvytlppsreemtknqvs 1tclvkgfypsdiavewesngqpennyktt ppvldsdgsfflyskitvdksrwqqgnvfs csvmhealhnhytqkslslspgk 1268. CD20-HLE scFc qvqlvqsgaevkkpgssvkvsckasgyafs yswinwvrqapgqglewmgrifpgdgdtdy ngkfkgrvtitadkststaymelsslrsed tavyycarnvfdgywlvywgqgtlvtvssg gggsggggsggggsdivmtqtplslpvtpg epasicrssksllhs ngitylywylqkpg qspql1iyqmsnlvsgvpdrfsgsgsgtdf tlkisrveaedvgvyycaqnlelpytfggg tkveiksggggsevqlvesggglvqpggsl klscaasgftfnkyamnwvrqapgkglewv arirskynnyatyyadsvkdrftisrddsk ntaylqmnnlkted tavyycvrhgnfgnsy isywaywgqgtlvtvssggggsggggsggg gsqtvvtqepsltvspggtvtltcgsstga vtsgnypnwvqqkpgqaprgliggtkflap gtparfsgsllggkaaltlsgvqpedeaey ycvlwysnrwvfgggtkltvl 1269. CD19 9-B7 VH CDR1 NYGMH

- 496 043309

CC x I2C0scFc 1270. CD19 9-B7 CC x I2C0- scFc VH CDR2 AIGWEGSNKYYAEPVKG 1271. CD19 9-B7 CC x I2C0- scFc VH CDR3 DRGTIFGYYGMDV 1272. CD19 9-B7 CC x I2C0scFc VL CDR1 RSSQSLLHSNRFNYLD 1273. CD19 9-B7 CC x I2C0- scFc VL CDR2 LGSNRAS 1274. CD19 9-B7 CC x I2C0- scFc VL CDR3 MQALQTPLT 1275. CD19 9-B7 CC x I2C0scFc VH QVQLVESGGGWQPGRSLRLSCEASGFIVS NYGMHWVRQAPGKCLEWVAAIGWEGSNKYY AEPVKGRFTISRDKSKNTLSLQMSSLRAED TALYYCARDRGTIFGYYGMDVWGQGTTVTV SS 1276. CD19 9-B7 CC x I2C0- scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HSNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPLTFACGTKVEIK 1277. CD19 9-B7 CC x I2C0- scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HSNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAAIGW EGSNKYYAEPV KGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSS

- 497 043309

1278. CD19 9-B7 CC x I2C0- scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HSNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAAIGW EGSNKYYAEPV KGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1279. CD19 9-B7 CC x I2C0scFc bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HSNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAAIGW EGSNKYYAEPV KGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI

-498 043309

SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQGNVFSCSVMHEALH NH YTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLV KGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1280. CD19 9-B7 CC x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HSNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAAIGW EGSNKYYAEPV KGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQG TLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYV DGVE

-499043309

VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSGGGGS GGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGS FFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1281. CD19 8-C2 CC x I2C0- scFc VH CDR1 SYGIH 1282. CD19 8-C2 CC x I2C0- scFc VH CDR2 LTSYEGGNKYYAESVKG 1283. CD19 8-C2 CC x I2C0- scFc VH CDR3 DRGTIFGDYGMDV 1284. CD19 8-C2 CC x I2C0- scFc VL CDR1 RSSQSLLHKNAFNYLD 1285. CD19 8-C2 CC x I2C0scFc VL CDR2 LGSNRAS 1286. CD19 8-C2 CC x I2C0- scFc VL CDR3 MQALQTPFT 1287. CD19 8-C2 CC x I2C0- scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT ES SYGIHWVRQAPGKCLEWVALTSYEGGNKYY AESVKGRFTISRDNSKNTLYLQMNSLRAED

- 500 043309

TAVYYCAKDRGTIFGDYGMDVWGQGTTVTV SS 1288. CD19 8-C2 CC x I2C0scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNAFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIK 1289. CD19 8-C2 CC x I2C0- scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNAFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSS 1290. CD19 8-C2 CC x I2C0- scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNAFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYW GQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1291. CD19 8-C2 CC x I2C0- scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNAFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV

- 501 043309

HLE YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESVKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CA AS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAAL TLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKN QVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTY RCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1292. CD19 8-C2 CC x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNAFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG

- 502 043309

GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESVKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRS KYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQGTLVTVSSGGGGSGGGGSG GGGSQTVVTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGG GTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTT PPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSGGGGSGGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNK AL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1293. CD19 8-C8 CC x I2C0- scFc VH CDR1 SYGIH 1294. CD19 8-C8 CC x I2C0- scFc VH CDR2 LTSYEGGNKYYAESVKG

- 503 043309

1295. CD19 8-C8 CC x I2C0- scFc VH CDR3 DRGTIFGDYGMDV 1296. CD19 8-C8 CC x I2C0- scFc VL CDR1 RSSQSLLHQNRFNYLD 1297. CD19 8-C8 CC x I2C0- scFc VL CDR2 LGSNRAS 1298. CD19 8-C8 CC x I2C0- scFc VL CDR3 MQALQTPFT 1299. CD19 8-C8 CC x I2C0- scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGIHWVRQAPGKCLEWVALTSYEGGNKYY AESVKGRFTISRDNSKNTLYLQMNSLRAED TAVYYCAKDRGTIFGDYGMDVWGQGTTVTV SS 1300. CD19 8-C8 CC x I2C0- scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HQNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIK 1301. CD19 8-C8 CC x I2C0- scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HQNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSS 1302. CD19 8-C8 CC x I2C0scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HQNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA

- 504 043309

ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESVKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNT AYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQGTLVTVSSGGGGSGGGGSG GGGSQTVVTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1303. CD19 8-C8 CC x I2C0- scFc bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HQNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWG QGTLVTVSSGGGGSGGGGSG GGGSQTVVTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNW YVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS

- 505 043309

FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEK TISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1304. CD19 8-C8 CC x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HQNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYW GQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFN WYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH

- 506 043309

TKNQV SLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1305. CD19 8-C9 CC x I2C0- scFc VH CDR1 SYGIH 1306. CD19 8-C9 CC x I2C0- scFc VH CDR2 LTSYEGGNKYYAESVKG 1307. CD19 8-C9 CC x I2C0- scFc VH CDR3 DRGTIFGDYGMEV 1308. CD19 8-C9 CC x I2C0- scFc VL CDR1 RSSQSLLHPNKLNYLD 1309. CD19 8-C9 CC x I2C0- scFc VL CDR2 LGSNRAS 1310. CD19 8-C9 CC x I2C0- scFc VL CDR3 MQALQTPFT 1311. CD19 8-C9 CC x I2C0- scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGIHWVRQAPGKCLEWVALTSYEGGNKYY AESVKGRFTISRDNSKNTLYLQMNSLRAED TAVYYCAKDRGTIFGDYGMEVWGQGTTVTV SS 1312. CD19 8-C9 CC x I2C0- scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HPNKLNYLDWYMQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV

- 507 043309

YYCMQALQTPFTFGCGTKVEIK 1313. CD19 8-C9 CC x I2C0- scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HPNKLNYLDWYMQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMEVWG QGTTVTVSS 1314. CD19 8-C9 CC x I2C0- scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HPNKLNYLDWYMQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWG QGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1315. CD19 8-C9 CC x I2C0- scFc bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HPNKLNYLDWYMQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMEVWG

- 508 043309

QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSG NYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCK VSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1316. CD19 8-C9 CC x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HPNKLNYLDWYMQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG

- 509 043309

APG TPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQV YTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSGGGGSGGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKT KPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1317. CD19 8-D1 CC x I2C0- scFc VH CDR1 SYGIH 1318. CD19 8-D1 CC x I2C0- scFc VH CDR2 LTSYEGGNKYYAESVKG 1319. CD19 8-D1 CC x I2C0- scFc VH CDR3 DRGTIFGDYGMDV 1320. CD19 8-D1 CC x I2C0- VL CDR1 RSSQSLLHKNRFNYLD

- 510 043309

scFc 1321. CD19 8-D1 CC x I2C0- scFc VL CDR2 LGSNRAS 1322. CD19 8-D1 CC x I2C0- scFc VL CDR3 MQALQTPFT 1323. CD19 8-D1 CC x I2C0- scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGIHWVRQAPGKCLEWVALTSYEGGNKYY AESVKGRFTISRDNSKNTLYLQMNSLRAED TAVYYCAKDRGTIFGDYGMDVWGQGTTVTV SS 1324. CD19 8-D1 CC x I2C0- scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNRFNYLDWYVQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIK 1325. CD19 8-D1 CC x I2C0- scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNRFNYLDWYVQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSS 1326. CD19 8-D1 CC x I2C0- scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNRFNYLDWYVQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE

-511 043309

WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYS NRWVFGGGTKLTVL 1327. CD19 8-D1 CC x I2C0- bispecifically cheskaya DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNRFNYLDWYVQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NS LRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYW GQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST scFc molecule HLE GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI S R T PE VT CVWDVS HE D PE VK FNW YVDGVE VHNAKTKPCEEQYGSTYRCVSVLTV LHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPK PKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY

- 512 043309

GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1328. CD19 8-D1 CC x I2C0scFc_delGK bispecifically cheskaya molecule HLE DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNRFNYLDWYVQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWG QGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNW YVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSGGGGSGGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL

- 513 043309

PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1329. CD19 9-A8 CC x I2C0- scFc VH CDR1 SYGIH 1330. CD19 9-A8 CC x I2C0scFc VH CDR2 LTSYEGGNKYYAESVKG 1331. CD19 9-A8 CC x I2C0scFc VH CDR3 DRGTIFGDYGMDV 1332. CD19 9-A8 CC x I2C0- scFc VL CDR1 RSSQSLLHRNSWNYLD 1333. CD19 9-A8 CC x I2C0- scFc VL CDR2 LGSNRAS 1334. CD19 9-A8 CC x I2C0- scFc VL CDR3 MQALQTPFT 1335. CD19 9-A8 CC x I2C0- scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGIHWVRQAPGKCLEWVALTSYEGGNKYY AESVKGRFTISRDNSKNTLYLQMNSLRAED TAVYYCAKDRGTIFGDYGMDVWGQGTTVTV SS 1336. CD19 9-A8 CC x I2C0- scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HRNSWNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIK 1337. CD19 9-A8 CC x I2C0- scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HRNSWNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG

- 514 043309

GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESVKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSS 1338. CD19 9-A8 CC x I2C0- scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HRNSWNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWG QGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1339. CD19 9-A8 CC x I2C0- scFc bispecific molecule HLE DIVMTQSPLSLPVTPGEPASISCRSSQSLL HRNSWNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG

- 515 043309

GGGSQTVVTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTK PCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTC PPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVD KSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1340. CD19 9-A8 CC x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HRNSWNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTVVTQEPSLTVSPGGTVTLTCGSST

- 516 043309

GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSGGGGSGGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMIS RTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHY TQKSLSLSPGK 1341. CD19 9-C1 CC x I2C0- scFc VH CDR1 SYGIH 1342. CD19 9-C1 CC x I2C0scFc VH CDR2 LTSYEGGNKYYAESVKG 1343. CD19 9-C1 CC x I2C0- scFc VH CDR3 DRGTIFGDYGMDV 1344. CD19 9-C1 CC x I2C0scFc VL CDR1 RSSQSLLHPNHFNYLD 1345. CD19 9-C1 CC x I2C0- scFc VL CDR2 LGSNRAS 1346. CD19 9-C1 VL CDR3 MQALQTPFT

-517043309

CC x I2C0scFc 1347. CD19 9-C1 CC x I2C0- scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGIHWVRQAPGKCLEWVALTSYEGGNKYY AESVKGRFTISRDNSKNTLYLQMNSLRAED TAVYYCAKDRGTIFGDYGMDVWGQGTTVTV SS 1348. CD19 9-C1 CC x I2C0- scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HPNHFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIK 1349. CD19 9-C1 CC x I2C0- scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HPNHFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSS 1350. CD19 9-C1 CC x I2C0scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HPNHFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWG QGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL

- 518 043309

APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1351. CD19 9-C1 CC x I2C0- scFc bispecifically cheskaya molecule HLE DIVMTQSPLSLPVTPGEPASISCRSSQSLL HPNHFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWY G GGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPV LDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG

- 519 043309

TO 1352. CD19 9-C1 CC x I2C0- scFc bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HPNHFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESV KGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWY G SGGGGSGGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPP VLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1353. CD19 0-B6 VH CDR1 SYGIH

- 520 043309

CC x I2C0scFc 1354. CD19 0-B6 CC x I2C0- scFc VH CDR2 LTSYEGGNKYYAESVKG 1355. CD19 0-B6 CC x I2C0- scFc VH CDR3 DRGTIFGDYGMDV 1356. CD19 0-B6 CC x I2C0scFc VL CDR1 RSSQSLLHKNSFNYLD 1357. CD19 0-B6 CC x I2C0- scFc VL CDR2 LGSNRAS 1358. CD19 0-B6 CC x I2C0- scFc VL CDR3 MQALQTPFT 1359. CD19 0-B6 CC x I2C0scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGIHWVRQAPGKCLEWVALTSYEGGNKYY AESVKGRFTISRDNSKNTLYLQMNSLRAED TAVYYCAKDRGTIFGDYGMDVWGQGTTVTV SS 1360. CD19 0-B6 CC x I2C0- scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNSFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIK 1361. CD19 0-B6 CC x I2C0- scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNSFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSS

- 521 043309

1362. CD19 0-B6 CC x I2C0- scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNSFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYW GQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1363. CD19 0-B6 CC x I2C0scFc bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNSFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYW GQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI

-522043309

SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQGNVFSCSVMHEALH NH YTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLV KGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1364. CD19 0-B6 CC x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNSFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWG QGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNW YVDGVE

-523 043309

VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSGGGGS GGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGS FFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1365. CD19 0-C12 CC x I2C0scFc VH CDR1 SYGIH 1366. CD19 0-C12 CC x I2C0scFc VH CDR2 LTSYEGGNKYYAESVKG 1367. CD19 0-C12 CC x I2C0scFc VH CDR3 DRGTIFGDYGMDV 1368. CD19 0-C12 CC x I2C0scFc VL CDR1 RSSQSLLHKNHFNYLD 1369. CD19 0-C12 CC x I2C0scFc VL CDR2 LGSNRAS 1370. CD19 0-C12 CC x I2C0scFc VL CDR3 MQALQTPFT 1371. CD19 0-C12 CC x I2C0scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGIHWVRQAPGKCLEWVALTSYEGGNKYY AESVKGRFTISRDNSKNTLYLQMNSLRAED

- 524 043309

TAVYYCAKDRGTIFGDYGMDVWGQGTTVTV SS 1372. CD19 0-C12 CC x I2C0scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNHFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIK 1373. CD19 0-C12 CC x I2C0scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNHFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSS 1374. CD19 0-C12 CC x I2C0scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNHFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAES VKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYW GQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1375. CD19 0-C12 CC x I2C0scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNHFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV

- 525 043309

HLE YYCMQALQTPFTFGCGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESVKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CA AS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAAL TLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKN QVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTY RCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1376. CD19 0-C12 CC x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNHFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVEIKGGGGSGGG

- 526 043309

GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGIHWVRQAPGKCLEWVALTSY EGGNKYYAESVKGRFTISRDNSKNTLYLQM NSLRAEDTAVYYCAKDRGTIFGDYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARI RSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVF GGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYK TTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSGGGGSGGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNK AL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1377. CD19 4- C1RE-B10 CC x I2C0-scFc VH CDR1 NYGMH 1378. CD19 4- C1RE-B10 CC x I2C0-scFc VH CDR2 VMSWEGSNKYYAEPVKG

- 527 043309

1379. CD19 4- C1RE-B10 CC x I2C0-scFc VH CDR3 DRGTIFGYYGMDV 1380. CD19 4- C1RE-B10 CC x I2C0-scFc VL CDR1 RSSQSLLHKNNFNYLD 1381. CD19 4- C1RE-B10 CC x I2C0-scFc VL CDR2 LGSNRAS 1382. CD19 4- C1RE-B10 CC x I2C0-scFc VL CDR3 MQALQTPLT 1383. CD19 4- C1RE-B10 CC x I2C0-scFc VH QVQLVESGGGWQPGRSLRLSCEASGFIVS NYGMHWVRQAPGKCLEWVAVMSWEGSNKYY AEPVKGRFTISRDKSKNTLSLQMSSLRAED TALYYCARDRGTIFGYYGMDVWGQGTTVTV SS 1384. CD19 4- C1RE-B10 CC x I2C0-scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPLTFACGTKVEIK 1385. CD19 4- C1RE-B10 CC x I2C0-scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAVMSW EGSNKYYAEPV KGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSS 1386. CD19 4- C1RE-B10 CC x I2C0-scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE

- 528 043309

ASGFIVSNYGMHWVRQAPGKCLEWVAVMSW EGSNKYYAEPVKGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAY LQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQGTLVTVSSGGGGSGGGGSG GGGSQTVVTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1387. CD19 4- C1RE-B10 CC x I2C0-scFc bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAVMSW EGSNKYYAEPV KGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQG TLVTVSSGGGGSGGGGSG GGGSQTVVTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYV DGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS

- 529 043309

FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEK TISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1388. CD19 4C1RE-B10 CC x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAVMSW EGSNKYYAEPV KGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWY VDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH

- 530 043309

TKNQV SLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1389. CD19 97- G1RE CC x I2C0-scFc VH CDR1 SYGMH 1390. CD19 97- G1RE CC x I2C0-scFc VH CDR2 VISYEGSNKYYAESVKG 1391. CD19 97- G1RE CC x I2C0-scFc VH CDR3 DRGTIFGNYGLEV 1392. CD19 97- G1RE CC x I2C0-scFc VL CDR1 RSSQSLLHGNRFNYLD 1393. CD19 97- G1RE CC x I2C0-scFc VL CDR2 LGSNRAS 1394. CD19 97- G1RE CC x I2C0-scFc VL CDR3 MQALQTPFT 1395. CD19 97- G1RE CC x I2C0-scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGMHWVRQAPGKCLEWVAVISYEGSNKYY AESVKGRFTISRDNSKNTLYLQMNSLRDED TAVYYCARDRGTIFGNYGLEVWGQGTTVTV SS 1396. CD19 97- G1RE CC x I2C0-scFc VL DIVMTQSPLSLPVISGEPASISCRSSQSLL HGNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV

- 531 043309

YYCMQALQTPFTFGCGTKVDIK 1397. CD19 97- G1RE CC x I2C0-scFc scFv DIVMTQSPLSLPVISGEPASISCRSSQSLL HGNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSS 1398. CD19 97- G1RE CC x I2C0-scFc bispecific molecule DIVMTQSPLSLPVISGEPASISCRSSQSLL HGNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1399. CD19 97- G1RE CC x I2C0-scFc bispecific HLE molecule DIVMTQSPLSLPVISGEPASISCRSSQSLL HGNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG

- 532 043309

QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSG NYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCK VSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1400. CD19 97- G1RE CC x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVISGEPASISCRSSQSLL HGNRFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDETAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG

- 533 043309

APG TPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQV YTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSGGGGSGGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKT KPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1401. CD19 97- G1RE-C2 CC x I2C0-scFc VH CDR1 SYGMH 1402. CD19 97- G1RE-C2 CC x I2C0-scFc VH CDR2 VISYEGSNKYYAESVKG 1403. CD19 97- G1RE-C2 CC x I2C0-scFc VH CDR3 DRGTIFGNYGLEV 1404. CD19 97- G1RE-C2 CC VL CDR1 RSSQSLLHKNAFNYLD

- 534 043309

x I2C0-scFc 1405. CD19 97- G1RE-C2 CC x I2C0-scFc VL CDR2 LGSNRAS 1406. CD19 97- G1RE-C2 CC x I2C0-scFc VL CDR3 MQALQTPFT 1407. CD19 97- G1RE-C2 CC x I2C0-scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGMHWVRQAPGKCLEWVAVISYEGSNKYY AESVKGRFTISRDNSKNTLYLQMNSLRDED TAVYYCARDRGTIFGNYGLEVWGQGTTVTV SS 1408. CD19 97- G1RE-C2 CC x I2C0-scFc VL DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNAFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIK 1409. CD19 97- G1RE-C2 CC x I2C0-scFc scFv DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNAFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSS 1410. CD19 97- G1RE-C2 CC x I2C0-scFc bispecific molecule DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNAFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDETAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE

- 535 043309

WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQGTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYS NRWVFGGGTKLTVL 1411. CD19 97- G1RE-C2 CC x I2C0-scFc bispecific HLE molecule DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNAFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQG TLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYV DGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGG SGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY

- 536 043309

GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1412. CD19 97G1RE-C2 CC x I2C0scFc_delGK bispecifically cheskaya molecule HLE DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNAFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQG TLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYV DGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSG GGGSGGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL

- 537 043309

PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1413. CD19 97- G1RE-B5 CC x I2C0-scFc VH CDR1 SYGMH 1414. CD19 97- G1RE-B5 CC x I2C0-scFc VH CDR2 VISYEGSNKYYAESVKG 1415. CD19 97- G1RE-B5 CC x I2C0-scFc VH CDR3 DRGTIFGNYGLEV 1416. CD19 97- G1RE-B5 CC x I2C0-scFc VL CDR1 RSSQSLLHKNKWNYLD 1417. CD19 97- G1RE-B5 CC x I2C0-scFc VL CDR2 LGSNRAS 1418. CD19 97- G1RE-B5 CC x I2C0-scFc VL CDR3 MQALQTPFT 1419. CD19 97- G1RE-B5 CC x I2C0-scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGMHWVRQAPGKCLEWVAVISYEGSNKYY AESVKGRFTISRDNSKNTLYLQMNSLRDED TAVYYCARDRGTIFGNYGLEVWGQGTTVTV SS 1420. CD19 97- G1RE-B5 CC x I2C0-scFc VL DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNKWNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIK 1421. CD19 97- G1RE-B5 CC x I2C0-scFc scFv DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNKWNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG

- 538 043309

GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAESVKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSS 1422. CD19 97- G1RE-B5 CC x I2C0-scFc bispecific molecule DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNKWNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1423. CD19 97- G1RE-B5 CC x I2C0-scFc bispecific molecule HLE DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNKWNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG

- 539 043309

GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTK PCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTC PPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GS TYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTV DKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1424. CD19 97- G1RE-B5 OS x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNKWNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NS LRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST

- 540 043309

GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW L NGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSGGGGSGGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRT PEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYT QKSLSLSPGK 1425. CD19 97- G1RE-B10 CC x I2C0-scFc VH CDR1 SYGMH 1426. CD19 97- G1RE-B10 CC x I2C0-scFc VH CDR2 VISYEGSNKYYAESVKG 1427. CD19 97- G1RE-B10 CC x I2C0-scFc VH CDR3 DRGTIFGNYGLEV 1428. CD19 97- G1RE-B10 CC x I2C0-scFc VL CDR1 RSSQSLLHKNNFNYLD 1429. CD19 97- G1RE-B10 CC x I2C0-scFc VL CDR2 LGSNRAS 1430. CD19 97- VL CDR3 MQALQTPFT

-541 043309

G1RE-B10 CC x I2C0-scFc 1431. CD19 97- G1RE-B10 CC x I2C0-scFc VH QVQLVE S GGGWQPGRS LRL S CAAS G FT FS SYGMHWVRQAPGKCLEWVAVISYEGSNKYY AESVKGRFTISRDNSKNTLYLQMNSLRDED TAVYYCARDRGTIFGNYGLEVWGQGTTVTV SS 1432. CD19 97- G1RE-B10 CC x I2C0-scFc VL DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIK 1433. CD19 97- G1RE-B10 CC x I2C0-scFc scFv DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSS 1434. CD19 97- G1RE-B10 CC x I2C0-scFc bispecific molecule DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS G FT FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL

- 542 043309

APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1435. CD19 97- G1RE-B10 CC x I2C0-scFc bispecific HLE molecule DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQG TLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYV DGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGKGGGGSGGGGSGGGGSG GGG SGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLD SDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG

- 543 043309

TO 1436. CD19 97G1RE-B10 CC x I2C0scFc_delGK bispecifically ical molecule HLE DIVMTQSPLSLPVISGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALQTPFTFGCGTKVDIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCA ASGFTFSSYGMHWVRQAPGKCLEWVAVISY EGSNKYYAES VKGRFTISRDNSKNTLYLQM NSLRDEDTAVYYCARDRGTIFGNYGLEVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQG TLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYV DGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSG GGGSGGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLD SDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1437. CD19 1-C3- VH CDR1 NYGMH

- 544 043309

BIO CC x I2C0-scFc 1438. CD19 1-C3- B10 CC x I2C0-scFc VH CDR2 AIGWEGSNKYYAEPVKG 1439. CD19 1-C3- B10 CC x I2C0-scFc VH CDR3 DRGTIFGYYGMDV 1440. CD19 1-C3- B10 CC x I2C0-scFc VL CDR1 RSSQSLLHKNNFNYLD 1441. CD19 1-C3- B10 CC x I2C0-scFc VL CDR2 LGSNRAS 1442. CD19 1-C3- B10 CC x I2C0-scFc VL CDR3 MQALSEPLT 1443. CD19 1-C3- B10 CC x I2C0-scFc VH QVQLVESGGGWQPGRSLRLSCEASGFIVS NYGMHWVRQAPGKCLEWVAAIGWEGSNKYY AEPVKGRFTISRDKSKNTLSLQMSSLRAED TALYYCARDRGTIFGYYGMDVWGQGTTVTV SS 1444. CD19 1-C3- B10 CC x I2C0-scFc VL DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALSEPLTFACGTKVEIK 1445. CD19 1-C3- B10 CC x I2C0-scFc scFv DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALSEPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAAIGW EGSNKYYAEP VKGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSS

- 545 043309

1446. CD19 1-NW- B10 CC x I2C0-scFc bispecific molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALSEPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAAIGW EGSNKYYAEP VKGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTVVTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVL 1447. CD19 1-C3- B10 CC x I2C0-scFc bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALSEPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAAIGW EGSNKYYAEP VKGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI

-546043309

SRTPEVTCVWDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQGNVFSCSVMHEALH NH YTQKSLSLSPGKGGGGSGGGGSGGGGSG GGGSGGGGSGGGGSDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVWDV SHEDPEVKFNWYVDGVEVHNAKTKPCEEQY GSTYRCVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLV KGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPG K 1448. CD19 1-NW- B10 CC x I2C0scFc_delGK bispecific HLE molecule DIVMTQSPLSLPVTPGEPASISCRSSQSLL HKNNFNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGV YYCMQALSEPLTFACGTKVEIKGGGGSGGG GSGGGGSQVQLVESGGGWQPGRSLRLSCE ASGFIVSNYGMHWVRQAPGKCLEWVAAIGW EGSNKYYAEP VKGRFTISRDKSKNTLSLQM S S LRAEDTALYYCARDRGTIFGYYGMDVWG QGTTVTVSSGGGGSEVQLVESGGGLVQPGG S LKL S CAAS GET FNKYAMNWVRQAPGKGLE WVARIRSKYNNYATYYADSVKDRFTISRDD SKNTAYLQMNNLKTEDTAVYYCVRHGNFGN SYISYWAYWGQ GTLVTVSSGGGGSGGGGSG GGGSQTWTQEPSLTVSPGGTVTLTCGSST GAVTSGNYPNWVQQKPGQAPRGLIGGTKFL APGTPARFSGSLLGGKAALTLSGVQPEDEA EYYCVLWYSNRWVFGGGTKLTVLGGGGDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWY VDGVE

-547043309

VHNAKTKPCEEQYGSTYRCVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGGGGSGGGGSGGGGSGGG GSGGGGS GGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPCEEQYGS TYRCVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGS FFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK 1449. IgGl hinge DKTHTCPPCP 1450. IgG2 hinge ERKCCVECPPCP 1451. IgG3 hinge ELKTPLDTTHTCPRCP 1452. IgG4 hinge ESKYGPPCPSCP 1453. EGFRvIIIccx 12С-hingeCH2-CH3linkerhinge-СН2СНЗ (DF9) bispecifically cheskaya molecule HLE QVQLVE S GGGWQS GRS LRL S CAAS G FT ER NYGMHWVRQAPGKCLEWVAVIWYDGSDKYY ADSVRGRFTISRDNSKNTLYLQMNSLRAED TAVYYCARDGYDILTGNPRDFDYWGQGTLV TVSSGGGGSGGGGSGGGGSDTVMTQTPLSS HVTLGQPASISCRSSQSLVHSDGNTYLSWL QQRPG QPPRLLIYRISRRFSGVPDRFSSGG AGTDFTLEISRVEAEDVGVYYCMQSTHVPR TFGCGTKVEIKSGGGGSEVQLVESGGGLVQ PGGSLKLSCAASGFTFNKYAMNWVRQAPGK GLEWVARIRSKYNNYATYYADSVKDRFTIS RDDSKNTAYLQMNNLKTEDTAVYYCVRHGN FGNSYISYWAYW GQGTLVTVSSGGGGSGGG GSGGGGSQTWTQEPSLTVSPGGTVTLTCG S S TGAVT S GNYPNWVQQKPGQAPRGLIGGT KFLAPGTPARFSGSLLGGKAALTLSGVQPE DEAEYYCVLWYSNRWVFGGGTKLTVLGGGG

-548 043309

DKTHTCPPCPAPELLGGPSVFLFPPKPKDT LMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPCEEQYGSTYRCVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLY SKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGKGGGGSGGGGSGGG GSGGGGSGGGGSGGGGSDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCW VDVSHEDPEVKFNWYVDGVEVHNAKTKPCE EQYGSTYRCVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEK TISKAKGQPREPQVYTLPP S RE EMT KNQVS L T C LVKG FY P S DIAVEWE S NGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK 1454. EGFRvIIIccx 12C-hingeCH2-CH3linker-CH2CH3 (T2G) bispecific HLE molecule QVQLVE S GGGWQS GRS LRL S CAAS G FT FR NYGMHWVRQAPGKCLEWVAVIWYDGSDKYY ADSVRGRFTISRDNSKNTLYLQMNSLRAED TAVYYCARDGYDILTGNPRDFDYWGQGTLV TVSSGGGGSGGGGSGGGGSDTVMTQTPLSS HVTLGQPASISCRSSQSLVHSDGNTYLSWL QQRPG QPPRLLIYRISRRFSGVPDRFSSGG AGTDFTLEISRVEAEDVGVYYCMQSTHVPR TFGCGTKVEIKSGGGGSEVQLVESGGGLVQ PGGSLKLSCAASGFTFNKYAMNWVRQAPGK GLEWVARIRSKYNNYATYYADSVKDRFTIS RDDSKNTAYLQMNNLKTEDTAVYYCVRHGN FGNSYISYWAYW GQGTLVTVSSGGGGSGGG GSGGGGSQTWTQEPSLTVSPGGTVTLTCG S S TGAVT S GNYPNWVQQKPGQAPRGLIGGT KFLAPGTPARFSGSLLGGKAALTLSGVQPE DEAEYYCVLWYSNRWVFGGGTKLTVLGGGG DKTHTCPPCPAPELLGGPSVFLFPPKPKDT

-549043309

LMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPCEEQYGSTYRCVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHE AL HNHYTQKSLSLSPGKGGGGSGGGGSGGG GSGGGGSGGGGSGGGGSAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVWDVSHEDPEV KFNWYVDGVEVHNAKTKPCEEQYGSTYRCV SVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGF YPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK 1455. EGFRvIIIccx 12С-hingeCH2-linkerhinge-СН2СНЗ-linkerСНЗ (D3L) bispecifically cheskaya molecule HLE QVQLVE S GGGWQS GRS LRL S CAAS G FT FR NYGMHWVRQAPGKCLEWVAVIWYDGSDKYY ADSVRGRFTISRDNSKNTLYLQMNSLRAED TAVYYCARDGYDILTGNPRDFDYWGQGTLV TVSSGGGGSGGGGSGGGGSDTVMTQTPLSS HVTLGQPASISCRSSQSLVHSDGNTYLSWL QQRPG QPPRLLIYRISRRFSGVPDRFSSGG AGTDFTLEISRVEAEDVGVYYCMQSTHVPR TFGCGTKVEIKSGGGGSEVQLVESGGGLVQ PGGSLKLSCAASGFTFNKYAMNWVRQAPGK GLEWVARIRSKYNNYATYYADSVKDRFTIS RDDSKNTAYLQMNNLKTEDTAVYYCVRHGN FGNSYISYWAYW GQGTLVTVSSGGGGSGGG GSGGGGSQTWTQEPSLTVSPGGTVTLTCG S S TGAVT S GNYPNWVQQKPGQAPRGLIGGT KFLAPGTPARFSGSLLGGKAALTLSGVQPE DEAEYYCVLWYSNRWVFGGGTKLTVLGGGG DKTHTCPPCPAPELLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHEDPEVKFN WYVD GVEVHNAKTKPCEEQYGSTYRCVSVLTVLH

-550 043309

QDWLNGKEYKCKVSNKALPAPIEKTI SKAK GGGGSGGGGSGGGGSGGGGSDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVT CVWDVSHEDPEVKFNWYVDGVEVHNAKTK PCEEQYGSTYRCVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREE MTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGKGGGGSGGGGSGGGGSGGGGSGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQG NVFSCSVMHEALH NHYTQKSLSLSPGK 1456. EGFRvIIIccx 12C-hingeCH2-linkerCH2-CHZlinker-CHZ (T7I) bispecific HLE molecule QVQLVE S GGGWQS GRS LRL S CAAS G FT ER NYGMHWVRQAPGKCLEWVAVIWYDGSDKYY ADSVRGRFTISRDNSKNTLYLQMNSLRAED TAVYYCARDGYDILTGNPRDFDYWGQGTLV TVSSGGGGSGGGGSGGGGSDTVMTQTPLSS HVTLGQPASISCRSSQSLVHSDGNTYLSWL QQRPG QPPRLLIYRISRRFSGVPDRFSSGG AGTDFTLEISRVEAEDVGVYYCMQSTHVPR TFGCGTKVEIKSGGGGSEVQLVESGGGLVQ PGGSLKLSCAASGFTFNKYAMNWVRQAPGK GLEWVARIRSKYNNYATYYADSVKDRFTIS RDDSKNTAYLQMNNLKTEDTAVYYCVRHGN FGNSYISYWAYW GQGTLVTVSSGGGGSGGG GSGGGGSQTWTQEPSLTVSPGGTVTLTCG S S TGAVT S GNYPNWVQQKPGQAPRGLIGGT KFLAPGTPARFSGSLLGGKAALTLSGVQPE DEAEYYCVLWYSNRWVFGGGTKLTVLGGGG DKTHTCPPCPAPELLGGPSVFLFPPKPKDT LMISRTPEVTCVWDVSHEDPEVKFNW YVD GVEVHNAKTKPCEEQYGSTYRCVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAK

- 551 043309

GGGGSGGGGSGGGGSGGGGSAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVWDVSHED PEVKFNWYVDGVEVHNAKTKPCEEQYGSTY RCVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSD SPGK 1457. EGFRvIIIccx I2C-CH2linker-CH2CH3-linkerCH3 (KbS) bispecifically cheskaya molecule HLE QVQLVE S GGGWQS GRS LRL S CAAS G FT FR NYGMHWVRQAPGKCLEWVAVIWYDGSDKYY ADSVRGRFTISRDNSKNTLYLQMNS LRAED TAVYYCARDGYDILTGNPRDFDYWGQGTLV TVSSGGGGSGGGGSGGGGSDTVMTQTPLSS HVTLGQPASISCRSSQSLVHSDGNTYLSWL QQRP GQPPRLLIYRISRRFSGVPDRFSGSG AGTDFTLEISRVEAEDVGVYYCMQSTHVPR TFGCGTKVEIKSGGGSEVQLVESGGGLVQ PGGSLKLSCAASGFTFNKYAMNWVRQAPGK GLEWVARIRSKYNNYATYYADSVKDRFTIS RDDSKNTAYLQMNNLKTEDTAVYYCVRHGN FGNSYISYWAY WGQGTLVTVSSGGGGSGGG GSGGGGSQTWTQEPSLTVSPGGTVTLTCG S S TGAVT S GNYPNWVQQKPGQAPRGLIGGT KFLAPGTPARFSGSLLGGKAALTLSGVQPE DEAEYYCVLWYSNRWVFGGGTKLTVLGGGG APELLGGPSVFLFPPKPKDTLMISRTPEVT CVWDVS HE D P E VK FNW YVD GVE VHNAKT K PCEEQYGSTYRCVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGGGGS GGGGS GGGGSGGGGSAPELLGGPSVFLFPPKPKDT LMIS RT PE VT CVWDVS HE D PE VK FNW YVD GVEVHNAKTKPCEEQYGSTYRCVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFS CSVMHE ALHNHYTQKSLSLSPGKGGGGSGGGGSGGG GSGGGGSGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK 1458. IgG3 hinge ELKTPLGDTTHTCPRCP 1459. IgGl hinge EPKSCDKTHTCPPCP

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Claims (14)

CLAIM 1. An extended half-life single chain bispecific antibody construct comprising at least three domains in order from amino to carboxy terminus, wherein the first domain binds to an antigen on the surface of a target cell, wherein the antigen on the surface of the target cell is a tumor antigen; the second domain binds to an extracellular epitope of the human and/or Macasa CD3ε chain; and the third domain contains two polypeptide monomers, each of which contains a hinge, a CH2 domain and a CH3 domain, wherein said two polypeptide monomers are fused to each other by a peptide linker, wherein said third domain contains, in order from amino to carboxy terminus: hinge-CH2-CH3-linker-hinge-CH2-CH3, wherein the CH2 domain contains an intradomain cysteine disulfide bridge, and where the first and second domains are fused to the third domain by a peptide linker. 2. The antibody construct of claim 1, wherein each of said polypeptide monomers has an amino acid sequence that is at least 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 17-24. 3. The antibody design of claim 2, wherein each of said polypeptide monomers has an amino acid sequence selected from SEQ ID NOs: 17-24. 4. Antibody construct according to claims 1-3, wherein the antibody construct contains, in order from amino to carboxy terminus: (a) first domain; (b) a peptide linker with an amino acid sequence selected from the group consisting of SEQ ID NO: 1-3; (c) second domain; (d) a peptide linker with an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 9, 10, 11 and 12; (e) the first polypeptide monomer of the third domain; (f) a peptide linker with an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6, 7 and 8; and (g) a second polypeptide monomer of the third domain. 5. The antibody design of claim 1, wherein the tumor antigen is selected from the group consisting of CDH19, MSLN, DLL3, FLT3, EGFRvIII, CD33, CD19, CD20 and CD70. 6. An antibody construct according to any one of the preceding claims, wherein the antibody construct comprises, in order from amino to carboxy terminus: (a) a first domain with an amino acid sequence selected from the group consisting of SEQ ID NO: 52, 70, 58, 76, 88, 106, 124, 94, 112, 130, 142,160, 178, 148, 166, 184, 196 , 214, 232, 202, 220, 238, 250, 266, 282, 298, 255, 271, 287, 303, 322, 338, 354, 370, 386, 402, 418, 434, 450, 466, 482, 498 , 514, 530, 546, 327, 343, 359, 375, 391, 407, 423, 439, 455, 471, 487, 503, 519, 353, 551, 592, 608, 624, 640, 656, 672, 688 , 704, 720, 736, 752, 768, 784, 800, 816, 832, 848, 864, 880, 896, 912, 928, 944, 960, 976, 992, 1008, 1024, 1040, 1056, 1072, 1088 , 1104, 1120, 1136, 1152, 1168, 1184, 597, 613, 629, 645, 661, 677, 693, 709, 725, 741, 757, 773, 789, 805, 821, 837, 853 , 869, 885 , 901, 917, 933, 949, 965, 981, 997, 1013, 1029, 1045, 1061, 1077, 1093, 1109, 1125, 1141, 1157, 1173, 1189,1277, 1289, 1 301, 1313, 1325, 1337 , 1349, 1361, 1373, 1385, 1397, 1409, 1421, 1433, 1445; (b) a peptide linker with an amino acid sequence selected from the group consisting of SEQ ID NO: 1-3; (c) a second domain with an amino acid sequence selected from the group consisting of SEQ ID NO: 23, 25, 41, 43, 59, 61, 77, 79, 95, 97, 113, 115, 131, 133, 149, 151 , 167, 169, 185 or 187 of WO 2008/119567 or SEQ ID NO: 15; (d) a peptide linker with an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 9, 10, 11 and 12; (e) a first polypeptide monomer of the third domain with a polypeptide sequence selected from the group consisting of SEQ ID NOs: 17-24; (f) a peptide linker with an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6, 7 and 8; and (g) a second polypeptide monomer of the third domain with a polypeptide sequence selected from the group consisting of SEQ ID NOs: 17-24. 7. Antibody design according to claim 6 with an amino acid sequence selected from the group consisting of: (a) SEQ ID NO: 54, 55, 60 and 61 for targeting CD33; (b) SEQ ID NO: 72, 73, 78 and 79 for targeting EGFRvIII; (c) SEQ ID NOs: 90, 91, 96, 97, 108, 109, 114 and 115 for targeting MSLN; (d) SEQ ID NO: 144, 145, 150, 151, 162, 163, 168, 169, 180, 181, 186 and 187; - 553 043309 (e) SEQ ID NO: 198, 199, 204, 205, 216, 217, 222, 223, 234, 235, 240 and 241 for targeting DLL3; (f) SEQ ID NO: 252, 306, 257, 307, 268, 308, 273, 309, 284, 310, 289, 311, 300, 312, 305 and 313 for targeting CDH19; (g) SEQ ID NO: 324, 554, 329, 555, 340, 556, 345, 557, 356, 558, 361, 559, 372, 560, 377, 561, 388, 562, 393, 563, 404, 564 , 409, 565, 420, 566, 425, 567, 436, 568, 441, 569, 452, 570, 457, 571, 468, 572, 473, 573, 484, 574, 489, 575, 500, 576, 505 , 577, 516, 578, 521, 579, 532, 580, 537, 581, 548, 582, 553, and 583 for targeting FLT3; (h) SEQ ID NO: 594, 610, 626, 642, 658, 674, 690, 706, 722, 738, 754, 77, 786, 802, 818, 834, 850, 866, 882, 898, 914, 930 , 946, 962, 978, 994, 1010, 1026, 1042, 1058, 1074, 1090, 1106, 1122, 1138, 1154, 1170, 1186, 599, 615, 631, 647, 663, 67 9, 695, 711, 727 , 743, 759, 775, 791, 807, 823, 839, 855, 871, 887, 903, 919, 935, 951, 967, 983, 999, 1015, 1031, 1047, 1063, 1079, 1095 , 1111, 1127 , 1143, 1159, 1175, 1191, and 1192-1267 to target CD70; (i) SEQ ID NO: 43 for targeting CD20; and (j) SEQ ID NO: 1279, 1280, 1291, 1292, 1303, 1304, 1315, 1316, 1327, 1328, 1339, 1340, 1351, 1352, 1363, 1364, 1375, 1376, 1387 , 1388, 1399, 1400, 1411, 1412, 1423, 1424, 1435, 1436, 1447, 1448 to target CD19. 8. A polynucleotide encoding an antibody construct as defined in any one of claims 1 to 7. 9. A host cell transformed or transfected with the polynucleotide defined in claim 8. 10. A method for producing an antibody construct according to any one of claims 1 to 7, including culturing a host cell according to claim 9 under conditions that ensure expression of the antibody construct according to any one of claims 1 to 7, and isolating the resulting antibody construct from the culture. 11. A pharmaceutical composition containing an antibody construct according to any one of claims 1 to 7 or obtained by a method according to claim 10 and one or more carriers, stabilizers, excipients, diluents, surfactants, emulsifiers, preservatives and/or adjuvants. 12. The pharmaceutical composition according to claim 11, which is stable for at least four weeks at approximately -20°C. 13. Use of an antibody construct according to any one of claims 1 to 7 or obtained by a method according to claim 10 for the preparation of a medicament for the treatment of a disease selected from a tumor disease, a viral disease or an immunological disorder. 14. A method for treating or reducing the intensity of a tumor disease, including the stage of administering to the patient an antibody construct according to any of claims 1-7 or obtained by the method according to claim 10.