Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Hyaluronidase: Difference between pages

{{Short description|Class of enzymes}}

{{Infobox enzyme|

| EC_number = 3.2.1.35

| CAS_number = 37326-33-3

| GO_code = 0004415

| image = Hyaluronidase 1 2PE4.png

| width =

| caption =

}}

{{Infobox protein family

| Symbol = Hyaluronidase_1

| image =

| width =

| caption = the partial structure of a group a streptococcal phage-encoded tail fibre hyaluronate lyase hylp2

| Pfam = PF07212

| Pfam_clan =

| InterPro = IPR009860

| SMART =

| PROSITE =

| MEROPS =

| SCOP =

| TCDB =

| OPM family =

| OPM protein =

| CAZy =

| CDD =

}}

{{Pfam box

| Symbol = Hyaluronidase_2

| drug_name = Hyaluronidase

| image =

| width =

| caption =

| Pfam= PF07555

| InterPro= IPR011496

| SMART=

| Prosite =

| SCOP =

| TCDB =

| OPM family =

| OPM protein =

| PDB =

}}

'''Hyaluronidases''' are a family of [[enzyme]]s that catalyse the degradation of [[hyaluronic acid]]. [[Karl Meyer (biochemist)|Karl Meyer]] classified these enzymes in 1971, into three distinct groups, a scheme based on the [[enzyme]] reaction products.<ref>{{cite book | vauthors = Meyer K |chapter= Hyaluronidases |publisher= Academic Press |editor= Boyer PD |title= Enzymes |volume= V |date= 1971 |location= New York |pages= 307–320 |isbn= 978-0-12-122705-0}}</ref> The three main types of hyaluronidases are two classes of eukaryotic endoglycosidase hydrolases and a prokaryotic lyase-type of [[glycosidase]].<ref>{{cite journal | vauthors = Stern R, Kogan G, Jedrzejas MJ, Soltés L | title = The many ways to cleave hyaluronan | journal = Biotechnology Advances | volume = 25 | issue = 6 | pages = 537–57 | date = November 2007 | pmid = 17716848 | doi = 10.1016/j.biotechadv.2007.07.001 }}</ref>

In humans, there are five functional hyaluronidases: [[HYAL1]], [[HYAL2]], [[HYAL3]], HYAL4 and HYAL5 (also known as [[SPAM1]] or PH-20); plus a [[pseudogene]], HYAL6 (also known as HYALP1).<ref name="ABC">{{cite journal | vauthors = Csóka AB, Scherer SW, Stern R | title = Expression analysis of six paralogous human hyaluronidase genes clustered on chromosomes 3p21 and 7q31 | journal = Genomics | volume = 60 | issue = 3 | pages = 356–61 | date = September 1999 | pmid = 10493834 | doi = 10.1006/geno.1999.5876 }}</ref><ref name="pmid11731267">{{cite journal | vauthors = Csoka AB, Frost GI, Stern R | title = The six hyaluronidase-like genes in the human and mouse genomes | journal = Matrix Biology | volume = 20 | issue = 8 | pages = 499–508 | date = December 2001 | pmid = 11731267 | doi = 10.1016/S0945-053X(01)00172-X }}</ref> The genes for HYAL1-3 are clustered in [[chromosome 3]], while HYAL4-6 are clustered in [[chromosome 7]].<ref name="ABC" /> HYAL1 and HYAL2 are the major hyaluronidases in most tissues. [[GPI-anchor]]ed HYAL2 is responsible for cleaving high-molecular weight hyaluronic acid, which is mostly bound to the [[CD44]] receptor. The resulting hyaluronic acid fragments of variable size are then further hydrolyzed by HYAL1 after being internalized into [[endosome|endo]]-[[lysosome]]s; this generates hyaluronic acid [[oligosaccharides]].<ref name="Chanmee">{{cite journal | vauthors = Chanmee T, Ontong P, Itano N | title = Hyaluronan: A modulator of the tumor microenvironment | journal = Cancer Letters | volume = 375 | issue = 1 | pages = 20–30 | date = May 2016 | pmid = 26921785 | doi = 10.1016/j.canlet.2016.02.031 }}</ref>

Hyaluronidases are '''hyaluronoglucosidases''' ({{EnzExplorer|3.2.1.35}}), i.e. they cleave the (1→4)-linkages between N-acetylglucosamine and glucuronate. The term hyaluronidase may also refer to [[hyaluronoglucuronidase]]s ({{EnzExplorer|3.2.1.36}}), which cleave (1→3)-linkages. In addition, bacterial hyaluronate lyases ({{EnzExplorer|4.2.2.1}}) may also be referred to as hyaluronidases, although this is uncommon.<ref>{{cite web|title=Hyaluronidase|url=http://enzyme.expasy.org/cgi-bin/enzyme/enzyme-search-de|website=ENZYME|publisher=ExPASy|access-date=17 November 2016}}</ref>

== Use as a drug ==

{{Infobox drug

| Verifiedfields = changed

| verifiedrevid = 461771405

| image =

| alt =

<!--Clinical data -->

| pronounce = {{IPAc-en|h|aɪ|(|ə|)|l|j|u|ˌ|r|ɑː|n|ɪ|ˈ|d|eɪ|s}}<ref>{{Cite Merriam-Webster|hyaluronidase|access-date=2020-07-03}}</ref>

| tradename = Hylenex, HyQvia, Vitrase, others

| Drugs.com = {{drugs.com|cons|hyaluronidase}}

| MedlinePlus =

| DailyMedID = Hyaluronidase

| pregnancy_AU =

| pregnancy_AU_comment = Exempt<ref name="Drugs.com pregnancy">{{cite web | title=Hyaluronidase Use During Pregnancy | website=Drugs.com | date=14 June 2019 | url=https://www.drugs.com/pregnancy/hyaluronidase.html | access-date=3 February 2020}}</ref>

| pregnancy_category=

| routes_of_administration = [[Subcutaneous injection|Subcutaneous]]

| ATC_supplemental = {{ATC|J06|BA01}}

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=ARTG ID 27749 Hyalase 1500IU powder for injection ampoule | website=Therapeutic Goods Administration (TGA) | url=http://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=27749 | access-date=9 August 2020 | archive-date=29 October 2021 | archive-url=https://web.archive.org/web/20211029024403/https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=27749 | url-status=dead }}</ref>

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled-->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment = <ref>{{cite web | title=Hyalase 1500 I.U. Powder for Solution for Injection/Infusion or Hyaluronidase 1500 I.U. Powder for Solution for Injection/Infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=12 March 2015 | url=https://www.medicines.org.uk/emc/product/1505/smpc | access-date=1 May 2020}}</ref><ref>{{cite web | title=HyQvia 100 mg/ml solution for infusion for subcutaneous use - Summary of Product Characteristics (SmPC) | website=(emc) | date=15 January 2020 | url=https://www.medicines.org.uk/emc/product/9197/smpc | access-date=1 May 2020}}</ref>

| legal_US = Rx-only

| legal_US_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->

| legal_UN_comment =

| legal_status = <!--For countries not listed above-->

<!-- Pharmacokinetic data -->

| bioavailability =

| protein_bound =

| metabolism =

| metabolites =

| onset =

| elimination_half-life =

| duration_of_action =

| excretion =

<!--Identifiers -->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 9001-54-1

| CAS_supplemental =

| PubChem =

| IUPHAR_ligand =

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00070

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = none

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 8KOG53Z5EM

| KEGG_Ref =

| KEGG = D04456

| KEGG2_Ref =

| KEGG2 = D04455

| ChEBI_Ref =

| ChEBI =

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1201636

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = hyaluronidase-fihj, hyaluronidase-oysk, hyaluronidase-zzxf

<!-- Chemical and physical data -->

| IUPAC_name = hyaluronidase

| C=2455 | H=3775 | N=617 | O=704 | S=21

| SMILES =

| StdInChI =

| StdInChI_comment =

| StdInChIKey =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

===Medical uses===

By [[catalysis|catalyzing]] the [[hydrolysis]] of [[hyaluronan]], a constituent of the [[extracellular matrix]], hyaluronidase lowers the [[viscosity]] of hyaluronan, thereby increasing [[biological tissue|tissue]] permeability. It is, therefore, used in medicine in conjunction with other [[medication|drugs]] to speed their dispersion and delivery. Common applications are [[ophthalmology|ophthalmic]] [[surgery]], in combination with [[local anesthetic]]s. It also increases the absorption rate of [[parenteral]] fluids given by [[hypodermoclysis]], and is an adjunct in subcutaneous [[urography]] for improving resorption of [[radiodensity|radiopaque]] agents. Hyaluronidase is also used for extravasation of hyperosmolar solutions. {{medcn|date=May 2020}} Besides, hyaluronidase is a recommended [[antidote]] for [[vinca alkaloid]] overdose or extravasation.<ref>{{cite web|title=Chemotherapy extravasation guideline|url=http://www.beatson.scot.nhs.uk/content/mediaassets/doc/Extravasation%20guidance.pdf|website=WOSCAN Cancer Nursing and Pharmacy Group|access-date=4 June 2017|date=September 2009|archive-date=27 January 2018|archive-url=https://web.archive.org/web/20180127143028/http://www.beatson.scot.nhs.uk/content/mediaassets/doc/Extravasation%20guidance.pdf|url-status=dead}}</ref> Hyaluronidase can be injected to dissolve hyaluronic acid type dermal fillers and is the best treatment option for those looking at dissolving lip filler or dealing with related complications.<ref>{{cite journal |vauthors=Borzabadi-Farahani A, Mosahebi A, Zargaran D |title=A Scoping Review of Hyaluronidase Use in Managing the Complications of Aesthetic Interventions|journal=Aesthetic Plastic Surgery |date= 2022 |volume=48 |issue=6 |pages=1193–1209 | pmid=36536092 | doi = 10.1007/s00266-022-03207-9|doi-access=free |pmc=10999391 }}</ref>

===Purified and recombinant hyaluronidases===

Four different purified hyaluronidases have been approved for use in the United States, three of animal origin and one recombinant. They are indicated as adjuvants in subcutaneous fluid administration for achieving hydration, for increasing the dispersion and absorption of other injected drugs, or for improving resorption of radiopaque agents, in subcutaneous urography.<ref name="Vitrase FDA label">{{cite web | title=Vitrase-hyaluronidase, ovine injection, solution | website=DailyMed | date=29 May 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=21fbd12e-4a12-4ad1-ad01-964cd5ec9996 | access-date=1 May 2020}}</ref><ref name="Amphadase FDA label">{{cite web | title=Amphadase- hyaluronidase injection | website=DailyMed | date=28 November 2016 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8396ea96-7cb5-4e26-87a4-90bca9c3c6dd | access-date=1 May 2020}}</ref><ref name="Hydase FDA label">{{cite web | title=Hydase- hyaluronidase injection, solution | website=DailyMed | date=16 November 2015 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5272b306-320a-4280-84aa-44f147ee73d4 | access-date=1 May 2020}}</ref>

The three naturally-sourced hyaluronidases are orthologs of human HYAL5 (PH20) obtained from testicular preparations. They are sold under the brand names Vitrase (ovine, FDA-approved in May 2004),<ref>{{cite web | title=Drug Approval Package: Vitrase (Hyaluronidase) NDA #021640 | website=U.S. [[Food and Drug Administration]] (FDA) | date=15 November 2004 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-640_Vitrase.cfm | access-date=1 May 2020}}</ref> Amphadase (bovine, October 2004)<ref>{{cite web | title=Drug Approval Package: Amphadase (Hyaluronidase) NDA #021665 | website=U.S. [[Food and Drug Administration]] (FDA) | date=4 February 2005 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-665_Amphadase.cfm | access-date=1 May 2020}}</ref> and Hydase (bovine, October 2005).<ref>{{cite web | title=Hydase: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | date=23 March 2020 | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021716 | access-date=1 May 2020}}</ref>

Human recombinant hyaluronidase (Hylenex Recombinant)—approved for use in the United States in December 2005<ref>{{cite web | title=Drug Approval Package: Hylenex Recombinant (Hyaluronidase) NDA #021859 | website=U.S. [[Food and Drug Administration]] (FDA) | date=3 January 2006 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021859_s000_HylenexTOC.cfm | access-date=1 May 2020}}</ref><ref name="urlHalozyme Therapeutics and Baxter Healthcare Corporation Announce FDA Approval of Hylenex">{{cite web|url=http://www.baxter.com/about_baxter/news_room/news_releases/2005/12-05-05-hylenex.html |title=Halozyme Therapeutics and Baxter Healthcare Corporation Announce FDA Approval of Hylenex |access-date=2008-11-07 |url-status=dead |archive-url=https://web.archive.org/web/20071018065242/http://baxter.com/about_baxter/news_room/news_releases/2005/12-05-05-hylenex.html |archive-date=October 18, 2007}}</ref>—corresponds to the soluble fragment of human HYAL5 (PH20) produced in [[cell culture|culture]] by genetically engineered [[Chinese hamster ovary cell]]s containing a DNA plasmid encoding the enzyme.<ref name="Hylenex FDA label">{{cite web | title=Hylenex recombinant (hyaluronidase- human recombinant injection), solution | website=DailyMed | date=1 January 2016 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3023cc56-ed4b-4e87-b3a1-81b20943f658 | access-date=1 May 2020}}</ref>

===Combination treatments===

A human recombinant hyaluronidase kit, HyQvia, was approved for use in the European Union in May 2013,<ref name="HyQvia EPAR">{{cite web | title=HyQvia EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/hyqvia | access-date=1 May 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> and in the United States in September 2014.<ref>{{cite web | title=Hyqvia | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm414117.htm | date=27 February 2015 | archive-date=22 July 2017 | archive-url=https://wayback.archive-it.org/7993/20170722071548/https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm414117.htm | access-date=1 May 2020 | url-status=dead }}</ref><ref name=fdahyq1>{{cite web | title=Hyqvia Approval Letter | url=https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm414148.htm | website=U.S. [[Food and Drug Administration]] (FDA) | access-date=20 November 2015 | archive-url=https://wayback.archive-it.org/7993/20170722071548/https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm414148.htm | archive-date=22 July 2017 | url-status=dead }}</ref> It is a dual vial unit with one vial of immune globulin infusion 10% (human) and one vial of recombinant human hyaluronidase.<ref name="Hyqvia FDA label">{{cite web | title=Hyqvia (immune globulin 10 percent- human with recombinant human hyaluronidase) kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7ca2c26f-4be2-48cd-be5b-486e350654ba | access-date=1 May 2020}}</ref> It is an immune globulin with a recombinant human hyaluronidase indicated in the United States for the treatment of [[primary immunodeficiency]] in adults. This includes, but is not limited to, common variable immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.<ref name="Hyqvia FDA label" /> In the European Union it is indicated as replacement therapy in adults, children and adolescents (0–18 years) in:

* Primary immunodeficiency syndromes with impaired antibody production.<ref name="HyQvia EPAR" />

* Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed or are contra‑indicated.<ref name="HyQvia EPAR" />

* Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients.<ref name="HyQvia EPAR" />

* Hypogammaglobulinaemia in patients pre‑ and post‑allogeneic hematopoietic stem cell transplantation.<ref name="HyQvia EPAR" />

A form of [[subcutaneous immunoglobulin]] (SCIG) that uses Hylenex to allow for a far greater volume of SCIG to be administered than would normally be possible to administer subcutaneously, providing a form of SCIG that can be dosed on a monthly basis, a longer period of time than other forms of SCIG allow. HyQvia had a rate of systemic adverse effects higher than traditional subcutaneous forms of immunoglobulin injection, but lower than those typical in [[IVIG]] patients.<ref name="biodrugs">{{cite journal|vauthors=Sanford M|date=August 2014|title=Human immunoglobulin 10 % with recombinant human hyaluronidase: replacement therapy in patients with primary immunodeficiency disorders|journal=BioDrugs|volume=28|issue=4|pages=411–20|doi=10.1007/s40259-014-0104-3|pmid=24925799|s2cid=8091134}}</ref> Also in [[epidural lysis of adhesions]] for pain management.{{medcn|date=May 2020}}

Hyaluronidase is available in some [[Combination drug|fixed-dose combination]] drug products in the United States: [[rituximab/hyaluronidase]] (Rituxan Hycela), [[trastuzumab/hyaluronidase|trastuzumab/hyaluronidase-oysk]] (Herceptin Hylecta), [[daratumumab/hyaluronidase|daratumumab/hyaluronidase-fihj]] (Darzalex Faspro), and [[pertuzumab/trastuzumab/hyaluronidase|pertuzumab/trastuzumab/hyaluronidase–zzxf]] (Phesgo).<ref>{{cite web | title=Drug Approval Package: Rituxan Hycela | website=U.S. [[Food and Drug Administration]] (FDA) | date=11 October 2018 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761064Orig1s000TOC.cfm | access-date=1 May 2020}}</ref><ref>{{cite web | title=Rituxan Hycela- rituximab and hyaluronidase injection, solution | website=DailyMed | date=3 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3e5b7e82-f018-4eaf-ae78-d6145a906b20 | access-date=1 May 2020}}</ref><ref>{{cite web | title=Drug Approval Package: Herceptin Hylecta | website=U.S. [[Food and Drug Administration]] (FDA) | date=17 October 2019 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761106Orig1s000TOC.cfm | access-date=1 May 2020}}</ref><ref>{{cite web | title=Herceptin Hylecta- trastuzumab and hyaluronidase-oysk injection, solution | website=DailyMed | date=13 May 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ebf30894-41cf-480c-8bc3-56f592a13813 | access-date=1 May 2020}}</ref><ref>{{cite web | title=Darzalex Faspro: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761145 | access-date=1 May 2020}}</ref><ref>{{cite press release | title=FDA Approves Breast Cancer Treatment That Can Be Administered At Home By Health Care Professional | website=U.S. Food and Drug Administration | date=29 June 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-breast-cancer-treatment-can-be-administered-home-health-care-professional | access-date=29 June 2020}}</ref><ref>{{cite web | title=FDA approves combination of pertuzumab, trastuzumab, and hyaluronidase | website=U.S. [[Food and Drug Administration]] (FDA) | date=29 June 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-combination-pertuzumab-trastuzumab-and-hyaluronidase-zzxf-her2-positive-breast-cancer | access-date=29 June 2020}}</ref>

In July 2021, the U.S. [[Food and Drug Administration]] (FDA) approved daratumumab and hyaluronidase-fihj in combination with pomalidomide and dexamethasone for adults with multiple myeloma who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor.<ref>{{cite web | title=FDA approves daratumumab and hyaluronidase-fihj with pomalidomide and | website=U.S. [[Food and Drug Administration]] (FDA) | date=12 July 2021 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-pomalidomide-and-dexamethasone-multiple-myeloma | access-date=12 July 2021}} {{PD-notice}}</ref>

[[Efgartigimod alfa/hyaluronidase]] (Vyvgart Hytrulo) was approved for the treatment of generalized [[myasthenia gravis]] in the United States in June 2023.<ref>{{cite press release | title=Halozyme Announces argenx Receives FDA Approval for Vyvgart Hytrulo With Enhanze for Subcutaneous Use in Generalized Myasthenia Gravis | publisher=Halozyme Therapeutics | via=PR Newswire | date=20 June 2023 | url=https://www.prnewswire.com/news-releases/halozyme-announces-argenx-receives-fda-approval-for-vyvgart-hytrulo-with-enhanze-for-subcutaneous-use-in-generalized-myasthenia-gravis-301855994.html | access-date=24 June 2023}}</ref><ref>{{cite press release | title=Argenx Announces U.S. Food and Drug Administration Approval of Vyvgart Hytrulo (efgartigimod alfa and hyaluronidase-qvfc) Injection for Subcutaneous Use in Generalized Myasthenia Gravis | website=Argenx | date=20 June 2023 | url=https://www.argenx.com/news/argenx-announces-us-food-and-drug-administration-approval-vyvgart-hytrulo-efgartigimod-alfa | access-date=24 June 2023}}</ref>

[[Ocrelizumab/hyaluronidase-ocsq]] (Ocrevus Zunovo) was approved for medical use in the United States in September 2024.<ref>{{cite press release | title=FDA Approves Ocrevus Zunovo as the First and Only Twice-A-Year 10-Minute Subcutaneous Injection for People With Relapsing and Progressive Multiple Sclerosis | website=Genentech | date=13 September 2024 | url=https://www.gene.com/media/press-releases/15036/2024-09-13/fda-approves-ocrevus-zunovo-as-the-first | access-date=13 September 2024}}</ref><ref>{{cite press release | title=Halozyme Announces FDA Approval of Roche's Subcutaneous Ocrevus Zunovo with Enhanze for People with Relapsing and Primary Progressive Multiple Sclerosis | publisher=Halozyme Therapeutics | via=PR Newswire | date=13 September 2024 | url=https://www.prnewswire.com/news-releases/halozyme-announces-fda-approval-of-roches-subcutaneous-ocrevus-zunovo-with-enhanze-for-people-with-relapsing-and-primary-progressive-multiple-sclerosis-302247928.html | access-date=13 September 2024}}</ref>

[[Atezolizumab/hyaluronidase-tqjs]] (Tecentriq Hybreza) was approved for medical use in the United States in September 2024.<ref name="FDA 20240912">{{cite web | title=FDA approves atezolizumab and hyaluronidase-tqjs | website=U.S. Food and Drug Administration | date=12 September 2024 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-and-hyaluronidase-tqjs-subcutaneous-injection | access-date=14 September 2024}} {{PD-notice}}}</ref><ref>{{cite press release | title=FDA Approves Genentech's Tecentriq Hybreza, the First and Only Subcutaneous Anti-PD-(L)1 Cancer Immunotherapy | website=Genentech | date=12 September 2024 | url=https://www.gene.com/media/press-releases/15035/2024-09-12/fda-approves-genentechs-tecentriq-hybrez | access-date=14 September 2024}}</ref><ref>{{cite press release | title=Halozyme Announces FDA Approval of Roche's Tecentriq Hybreza With Enhanze for Multiple Types of Cancer | publisher=Halozyme Therapeutics | via=PR Newswire | date=12 September 2024 | url=https://www.prnewswire.com/news-releases/halozyme-announces-fda-approval-of-roches-tecentriq-hybreza-with-enhanze-for-multiple-types-of-cancer-302247280.html | access-date=14 September 2024}}</ref>

== Role in cancer ==

The role of hyaluronidases in cancer has been historically controversial due to contradictory observations,<ref>{{cite journal | vauthors = Whatcott CJ, Han H, Posner RG, Hostetter G, Von Hoff DD | title = Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look | journal = Cancer Discovery | volume = 1 | issue = 4 | pages = 291–6 | date = September 2011 | pmid = 22053288 | pmc = 3204883 | doi = 10.1158/2159-8290.CD-11-0136 }}</ref> namely that levels of hyaluronidase (HYAL1/2) are increased in some cancers ([[colorectal cancer|colorectal]],<ref>{{cite journal | vauthors = Bouga H, Tsouros I, Bounias D, Kyriakopoulou D, Stavropoulos MS, Papageorgakopoulou N, Theocharis DA, Vynios DH | display-authors = 6 | title = Involvement of hyaluronidases in colorectal cancer | journal = BMC Cancer | volume = 10 | issue = 1 | pages = 499 | date = September 2010 | pmid = 20849597 | pmc = 2949809 | doi = 10.1186/1471-2407-10-499 | publisher = Springer Nature | doi-access = free }}</ref> bladder, prostate, breast and brain), whereas low expression of HYAL1 is correlated with a decrease in survival of [[pancreatic adenocarcinoma]] patients.<ref name="Prognostic impact of hyaluronan and its regulators in pancreatic ductal adenocarcinoma">{{cite journal | vauthors = Cheng XB, Sato N, Kohi S, Yamaguchi K | title = Prognostic impact of hyaluronan and its regulators in pancreatic ductal adenocarcinoma | journal = PLOS ONE | volume = 8 | issue = 11 | pages = e80765 | date = 2013 | pmid = 24244714 | pmc = 3823618 | doi = 10.1371/journal.pone.0080765 | bibcode = 2013PLoSO...880765C | doi-access = free }}</ref> The reason for this apparent contradiction is that both the accumulation of hyaluronic acid (due to increased [[hyaluronan synthase]] levels and decreased HYAL levels) and the degradation of hyaluronic acid into hyaluronic acid oligosaccharides by high HYAL levels result in increased tumor malignancy.<ref name="Chanmee" />

Elevated tissue expression of hyaluronic acid and hyaluronidase validates the hyaluronic acid-hyaluronidases urine test for bladder cancer.<ref>{{cite journal | vauthors = Hautmann SH, Lokeshwar VB, Schroeder GL, Civantos F, Duncan RC, Gnann R, Friedrich MG, Soloway MS | title = Elevated tissue expression of hyaluronic acid and hyaluronidase validates the HA-HAase urine test for bladder cancer | journal = The Journal of Urology | volume = 165 | issue = 6 Pt 1 | pages = 2068–74 | date = June 2001 | pmid = 11371930 | doi = 10.1016/s0022-5347(05)66296-9 }}</ref> Limited data support a role of lysosomal hyaluronidases in metastasis, while other data support a role in tumor suppression. Other studies suggest no contribution or effects independent of enzyme activity. Non-specific inhibitors (apigenin, sulfated [[glycosaminoglycan]]s) or crude enzyme extracts have been used to test most hypotheses, making data difficult to interpret. It has been hypothesized that, by helping degrade the extracellular matrix surrounding the tumor, hyaluronidases help cancer cells escape from primary tumor masses. However, studies show that removal of hyaluronan from tumors prevents tumor invasion.{{citation needed|date=December 2016}} Hyaluronidases are also thought to play a role in the process of [[angiogenesis]], although most hyaluronidase preparations are contaminated with large amounts of angiogenic growth factors.<ref>{{cite journal | vauthors = Rahmanian M, Heldin P | title = Testicular hyaluronidase induces tubular structures of endothelial cells grown in three-dimensional collagen gel through a CD44-mediated mechanism | journal = International Journal of Cancer | volume = 97 | issue = 5 | pages = 601–7 | date = February 2002 | pmid = 11807784 | doi = 10.1002/ijc.10087 | s2cid = 46736648 | doi-access = free }}</ref>

== Role in pathogenesis ==

Some bacteria, such as ''[[Staphylococcus aureus]]'', ''[[Streptococcus pyogenes]]'',<ref name="pmid16368955">{{cite journal | vauthors = Starr CR, Engleberg NC | title = Role of hyaluronidase in subcutaneous spread and growth of group A streptococcus | journal = Infection and Immunity | volume = 74 | issue = 1 | pages = 40–8 | date = January 2006 | pmid = 16368955 | pmc = 1346594 | doi = 10.1128/IAI.74.1.40-48.2006 }}</ref> and ''[[Clostridium perfringens]]'',<ref name="pmid10747251">{{cite journal | vauthors = Zukaite V, Biziulevicius GA | title = Acceleration of hyaluronidase production in the course of batch cultivation of Clostridium perfringens can be achieved with bacteriolytic enzymes | journal = Letters in Applied Microbiology | volume = 30 | issue = 3 | pages = 203–6 | date = March 2000 | pmid = 10747251 | doi = 10.1046/j.1472-765x.2000.00693.x | doi-access = free }}</ref> produce hyaluronidase as a means of using hyaluronan as a carbon source. It is often speculated that ''Streptococcus'' and ''Staphylococcus'' pathogens use hyaluronidase as a [[virulence factor]] to destroy the polysaccharide that holds animal cells together, making it easier for the pathogen to spread through the tissues of the host organism, but no valid experimental data are available to support this hypothesis.{{cn|date=May 2024}}

Hyaluronidases are found in the [[venom]] of certain lizards and snakes, as well as honeybees, where they are referred to as "spreading factors", having a function akin to bacterial hyaluronidases.<ref>{{cite journal | vauthors = Isoyama T, Thwaites D, Selzer MG, Carey RI, Barbucci R, Lokeshwar VB | title = Differential selectivity of hyaluronidase inhibitors toward acidic and basic hyaluronidases | journal = Glycobiology | volume = 16 | issue = 1 | pages = 11–21 | date = January 2006 | pmid = 16166602 | doi = 10.1093/glycob/cwj036 | doi-access = free }}</ref>

== Role in immune response ==

White blood cells produce hyaluronidase to move more easily through connective tissue to get to infected sites.<ref>{{Cite book|title=Principles of anatomy & physiology| vauthors = Tortora GJ, Derrickson B |isbn=978-1-118-34500-9|edition=14th|location=Danvers, MA|oclc=871018672|date=2013-12-31|url-access=registration|url=https://archive.org/details/principlesofanat0000tort}}</ref>

== Role in sepsis and septic shock ==

Plasma [[hyaluronic acid]] is elevated in [[sepsis]] and [[septic shock]] and correlate with disease severity, but the effect on mortality shows conflicting results.<ref>{{cite journal | vauthors = Anand D, Ray S, Srivastava LM, Bhargava S | title = Evolution of serum hyaluronan and syndecan levels in prognosis of sepsis patients | journal = Clinical Biochemistry | volume = 49 | issue = 10–11 | pages = 768–776 | date = July 2016 | pmid = 26953518 | doi = 10.1016/j.clinbiochem.2016.02.014 }}</ref><ref>{{cite journal | vauthors = Yagmur E, Koch A, Haumann M, Kramann R, Trautwein C, Tacke F | title = Hyaluronan serum concentrations are elevated in critically ill patients and associated with disease severity | journal = Clinical Biochemistry | volume = 45 | issue = 1–2 | pages = 82–87 | date = January 2012 | pmid = 22085533 | doi = 10.1016/j.clinbiochem.2011.10.016 }}</ref> Hyaluronidase, when injected into the circulation, results in the loss of [[glycocalyx]]<ref>{{cite journal | vauthors = Landsverk SA, Tsai AG, Cabrales P, Intaglietta M | title = Impact of enzymatic degradation of the endothelial glycocalyx on vascular permeability in an awake hamster model | journal = Critical Care Research and Practice | volume = 2012 | pages = 842545 | date = 2012 | pmid = 22792450 | pmc = 3389652 | doi = 10.1155/2012/842545 | doi-access = free }}</ref> and is therefore considered as a potential endogenous sheddase.<ref>{{cite journal | vauthors = Becker BF, Jacob M, Leipert S, Salmon AH, Chappell D | title = Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases | journal = British Journal of Clinical Pharmacology | volume = 80 | issue = 3 | pages = 389–402 | date = September 2015 | pmid = 25778676 | pmc = 4574825 | doi = 10.1111/bcp.12629 }}</ref> However, plasma hyaluronidase activity is decreased in experimental as well as in clinical septic shock.<ref>{{cite journal | vauthors = van der Heijden J, Kolliopoulos C, Skorup P, Sallisalmi M, Heldin P, Hultström M, Tenhunen J | title = Plasma hyaluronan, hyaluronidase activity and endogenous hyaluronidase inhibition in sepsis: an experimental and clinical cohort study | journal = Intensive Care Medicine Experimental | volume = 9 | issue = 1 | pages = 53 | date = October 2021 | pmid = 34632531 | pmc = 8502523 | doi = 10.1186/s40635-021-00418-3 | doi-access = free }}</ref> Concomitant, the endogenous hyaluronidase inhibition in plasma was increased and may explain to certain extent the decreased plasma hyaluronidase activity.{{cn|date=May 2024}}

== Role in fertilization ==

In mammalian [[fertilization]], hyaluronidase is released by the [[acrosome]] of the [[spermatozoon|sperm cell]] after it has reached the [[oocyte]], by digesting hyaluronan in the [[corona radiata (embryology)|corona radiata]], thus enabling [[conception (biology)|conception]]. Gene-targeting studies show that hyaluronidases such as PH20 are not essential for fertilization,<ref name="Baba">{{cite journal | vauthors = Baba D, Kashiwabara S, Honda A, Yamagata K, Wu Q, Ikawa M, Okabe M, Baba T | title = Mouse sperm lacking cell surface hyaluronidase PH-20 can pass through the layer of cumulus cells and fertilize the egg | journal = The Journal of Biological Chemistry | volume = 277 | issue = 33 | pages = 30310–4 | date = August 2002 | pmid = 12065596 | doi = 10.1074/jbc.M204596200 | doi-access = free }}</ref> although exogenous hyaluronidases can disrupt the cumulus matrix.

The majority of mammalian ova are covered in a layer of [[granulosa cell]]s intertwined in an extracellular matrix that contains a high concentration of hyaluronan. When a [[capacitation|capacitated]] sperm reaches the ovum, it is able to penetrate this layer with the assistance of hyaluronidase enzymes present on the surface of the sperm. Once this occurs, the sperm is capable of binding with the [[zona pellucida]].<ref name="isbn0-8153-4105-9">{{cite book | last = Alberts | first = Bruce | name-list-style = vanc |title= Molecular biology of the cell |publisher= Garland Science |location= New York |year= 2008 |pages= 1298 |isbn= 978-0-8153-4105-5}}</ref>

== References ==

{{Reflist}}

== External links ==

* {{Commons category-inline}}

* {{MeshName|Hyaluronidase}}

{{Sugar hydrolases}}

{{Enzymes}}

{{Portal bar|Biology|Medicine|border=no}}

[[Category:EC 3.2.1]]

[[Category:Extracellular matrix remodeling enzymes]]