Hyaluronidase Explained

Ec Number:3.2.1.35
Cas Number:37326-33-3
Go Code:0004415
Symbol:Hyaluronidase_1
Pfam:PF07212
Interpro:IPR009860

Hyaluronidases are a family of enzymes that catalyse the degradation of hyaluronic acid. Karl Meyer classified these enzymes in 1971, into three distinct groups, a scheme based on the enzyme reaction products.[1] The three main types of hyaluronidases are two classes of eukaryotic endoglycosidase hydrolases and a prokaryotic lyase-type of glycosidase.[2]

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).[3] [4] The genes for HYAL1-3 are clustered in chromosome 3, while HYAL4-6 are clustered in chromosome 7. HYAL1 and HYAL2 are the major hyaluronidases in most tissues. GPI-anchored 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 endo-lysosomes; this generates hyaluronic acid oligosaccharides.[5]

Hyaluronidases are hyaluronoglucosidases, i.e. they cleave the (1→4)-linkages between N-acetylglucosamine and glucuronate. The term hyaluronidase may also refer to hyaluronoglucuronidases, which cleave (1→3)-linkages. In addition, bacterial hyaluronate lyases may also be referred to as hyaluronidases, although this is uncommon.[6]

Use as a drug

Verifiedfields:changed
Verifiedrevid:461771405
Pronounce:[7]
Tradename:Hylenex, HyQvia, Vitrase, others
Dailymedid:Hyaluronidase
Pregnancy Au Comment:Exempt[8]
Routes Of Administration:Subcutaneous
Atc Prefix:B06
Atc Suffix:AA03
Legal Au:S4
Legal Au Comment:[9]
Legal Uk:POM
Legal Uk Comment:[10] [11]
Legal Us:Rx-only
Cas Number:9001-54-1
Drugbank:DB00070
Chemspiderid:none
Unii:8KOG53Z5EM
Kegg:D04456
Kegg2:D04455
Chembl:1201636
Synonyms:hyaluronidase-fihj, hyaluronidase-oysk, hyaluronidase-zzxf
Iupac Name:hyaluronidase
C:2455
H:3775
N:617
O:704
S:21

Medical uses

By catalyzing the hydrolysis of hyaluronan, a constituent of the extracellular matrix, hyaluronidase lowers the viscosity of hyaluronan, thereby increasing tissue permeability. It is, therefore, used in medicine in conjunction with other drugs to speed their dispersion and delivery. Common applications are ophthalmic surgery, in combination with local anesthetics. It also increases the absorption rate of parenteral fluids given by hypodermoclysis, and is an adjunct in subcutaneous urography for improving resorption of radiopaque agents. Hyaluronidase is also used for extravasation of hyperosmolar solutions. Besides, hyaluronidase is a recommended antidote for vinca alkaloid overdose or extravasation.[12] 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.[13]

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.[14] [15] [16]

The three naturally-sourced hyaluronidases are orthologs of human HYAL5 (PH20) obtained from testicular preparations. They are sold under the trade names Vitrase (ovine, FDA-approved in May 2004),[17] Amphadase (bovine, October 2004)[18] and Hydase (bovine, October 2005).[19]

Human recombinant hyaluronidase (Hylenex)—approved for use in the United States in December 2005[20] [21] —corresponds to the soluble fragment of human HYAL5 (PH20) produced in culture by genetically engineered Chinese hamster ovary cells containing a DNA plasmid encoding the enzyme.[22]

Combination treatments

A human recombinant hyaluronidase kit, HyQvia, was approved for use in the European Union in May 2013,[23] and in the United States in September 2014.[24] [25] It is a dual vial unit with one vial of immune globulin infusion 10% (human) and one vial of recombinant human hyaluronidase.[26] 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. In the European Union it is indicated as replacement therapy in adults, children and adolescents (0–18 years) in:

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.[27] Also in epidural lysis of adhesions for pain management.

Hyaluronidase is available in some fixed-dose combination drug products in the United States: rituximab/hyaluronidase (Rituxan Hycela), trastuzumab/hyaluronidase-oysk (Herceptin Hylecta), daratumumab/hyaluronidase-fihj (Darzalex Faspro), and pertuzumab/trastuzumab/hyaluronidase–zzxf (Phesgo).[28] [29] [30] [31] [32] [33] [34]

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.[35]

Efgartigimod alfa/hyaluronidase (Vyvgart Hytrulo) was approved for the treatment of generalized myasthenia gravis in the United States in June 2023.[36] [37]

Role in cancer

The role of hyaluronidases in cancer has been historically controversial due to contradictory observations,[38] namely that levels of hyaluronidase (HYAL1/2) are increased in some cancers (colorectal,[39] bladder, prostate, breast and brain), whereas low expression of HYAL1 is correlated with a decrease in survival of pancreatic adenocarcinoma patients.[40] 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.

Elevated tissue expression of hyaluronic acid and hyaluronidase validates the hyaluronic acid-hyaluronidases urine test for bladder cancer.[41] 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 glycosaminoglycans) 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. 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.[42]

Role in pathogenesis

Some bacteria, such as Staphylococcus aureus, Streptococcus pyogenes,[43] and Clostridium perfringens,[44] 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.

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.[45]

Role in immune response

White blood cells produce hyaluronidase to move more easily through connective tissue to get to infected sites.[46]

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.[47] [48] Hyaluronidase, when injected into the circulation, results in the loss of glycocalyx[49] and is therefore considered as a potential endogenous sheddase.[50] However, plasma hyaluronidase activity is decreased in experimental as well as in clinical septic shock.[51] Concomitant, the endogenous hyaluronidase inhibition in plasma was increased and may explain to certain extent the decreased plasma hyaluronidase activity.

Role in fertilization

In mammalian fertilization, hyaluronidase is released by the acrosome of the sperm cell after it has reached the oocyte, by digesting hyaluronan in the corona radiata, thus enabling conception. Gene-targeting studies show that hyaluronidases such as PH20 are not essential for fertilization,[52] although exogenous hyaluronidases can disrupt the cumulus matrix.

The majority of mammalian ova are covered in a layer of granulosa cells intertwined in an extracellular matrix that contains a high concentration of hyaluronan. When a 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.[53]

Notes and References

  1. Book: Meyer K . Hyaluronidases . Academic Press . Boyer PD . Enzymes . V . 1971 . New York . 307–320 . 978-0-12-122705-0.
  2. Stern R, Kogan G, Jedrzejas MJ, Soltés L . The many ways to cleave hyaluronan . Biotechnology Advances . 25 . 6 . 537–57 . November 2007 . 17716848 . 10.1016/j.biotechadv.2007.07.001 .
  3. Csóka AB, Scherer SW, Stern R . Expression analysis of six paralogous human hyaluronidase genes clustered on chromosomes 3p21 and 7q31 . Genomics . 60 . 3 . 356–61 . September 1999 . 10493834 . 10.1006/geno.1999.5876 .
  4. Csoka AB, Frost GI, Stern R . The six hyaluronidase-like genes in the human and mouse genomes . Matrix Biology . 20 . 8 . 499–508 . December 2001 . 11731267 . 10.1016/S0945-053X(01)00172-X .
  5. Chanmee T, Ontong P, Itano N . Hyaluronan: A modulator of the tumor microenvironment . Cancer Letters . 375 . 1 . 20–30 . May 2016 . 26921785 . 10.1016/j.canlet.2016.02.031 .
  6. Web site: Hyaluronidase. ENZYME. ExPASy. 17 November 2016.
  7. 2020-07-03.
  8. Web site: Hyaluronidase Use During Pregnancy . Drugs.com . 14 June 2019 . 3 February 2020.
  9. Web site: ARTG ID 27749 Hyalase 1500IU powder for injection ampoule . Therapeutic Goods Administration (TGA) . 9 August 2020 . 29 October 2021 . https://web.archive.org/web/20211029024403/https://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=27749 . dead .
  10. Web site: 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) . (emc) . 12 March 2015 . 1 May 2020.
  11. Web site: HyQvia 100 mg/ml solution for infusion for subcutaneous use - Summary of Product Characteristics (SmPC) . (emc) . 15 January 2020 . 1 May 2020.
  12. Web site: Chemotherapy extravasation guideline. WOSCAN Cancer Nursing and Pharmacy Group. 4 June 2017. September 2009. 27 January 2018. https://web.archive.org/web/20180127143028/http://www.beatson.scot.nhs.uk/content/mediaassets/doc/Extravasation%20guidance.pdf. dead.
  13. Borzabadi-Farahani A, Mosahebi A, Zargaran D . A Scoping Review of Hyaluronidase Use in Managing the Complications of Aesthetic Interventions. Aesthetic Plastic Surgery . 2022 . 48 . 6 . 1193–1209 . 36536092 . 10.1007/s00266-022-03207-9. free . 10999391 .
  14. Web site: Vitrase-hyaluronidase, ovine injection, solution . DailyMed . 29 May 2018 . 1 May 2020.
  15. Web site: Amphadase- hyaluronidase injection . DailyMed . 28 November 2016 . 1 May 2020.
  16. Web site: Hydase- hyaluronidase injection, solution . DailyMed . 16 November 2015 . 1 May 2020.
  17. Web site: Drug Approval Package: Vitrase (Hyaluronidase) NDA #021640 . U.S. Food and Drug Administration (FDA) . 15 November 2004 . 1 May 2020.
  18. Web site: Drug Approval Package: Amphadase (Hyaluronidase) NDA #021665 . U.S. Food and Drug Administration (FDA) . 4 February 2005 . 1 May 2020.
  19. Web site: Hydase: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA) . 23 March 2020 . 1 May 2020.
  20. Web site: Drug Approval Package: Hylenex Recombinant (Hyaluronidase) NDA #021859 . U.S. Food and Drug Administration (FDA) . 3 January 2006 . 1 May 2020.
  21. Web site: Halozyme Therapeutics and Baxter Healthcare Corporation Announce FDA Approval of Hylenex . 2008-11-07 . dead . https://web.archive.org/web/20071018065242/http://baxter.com/about_baxter/news_room/news_releases/2005/12-05-05-hylenex.html . October 18, 2007.
  22. Web site: Hylenex recombinant (hyaluronidase- human recombinant injection), solution . DailyMed . 1 January 2016 . 1 May 2020.
  23. Web site: HyQvia EPAR . European Medicines Agency (EMA) . 17 September 2018 . 1 May 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  24. Web site: Hyqvia . U.S. Food and Drug Administration (FDA) . 27 February 2015 . 22 July 2017 . https://wayback.archive-it.org/7993/20170722071548/https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm414117.htm . 1 May 2020 . dead .
  25. Web site: Hyqvia Approval Letter . U.S. Food and Drug Administration (FDA) . 20 November 2015 . https://wayback.archive-it.org/7993/20170722071548/https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm414148.htm . 22 July 2017 . dead .
  26. Web site: Hyqvia (immune globulin 10 percent- human with recombinant human hyaluronidase) kit . DailyMed . 1 May 2020.
  27. Sanford M. August 2014. Human immunoglobulin 10 % with recombinant human hyaluronidase: replacement therapy in patients with primary immunodeficiency disorders. BioDrugs. 28. 4. 411–20. 10.1007/s40259-014-0104-3. 24925799. 8091134.
  28. Web site: Drug Approval Package: Rituxan Hycela . U.S. Food and Drug Administration (FDA) . 11 October 2018 . 1 May 2020.
  29. Web site: Rituxan Hycela- rituximab and hyaluronidase injection, solution . DailyMed . 3 December 2019 . 1 May 2020.
  30. Web site: Drug Approval Package: Herceptin Hylecta . U.S. Food and Drug Administration (FDA) . 17 October 2019 . 1 May 2020.
  31. Web site: Herceptin Hylecta- trastuzumab and hyaluronidase-oysk injection, solution . DailyMed . 13 May 2019 . 1 May 2020.
  32. Web site: Darzalex Faspro: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA) . 1 May 2020.
  33. FDA Approves Breast Cancer Treatment That Can Be Administered At Home By Health Care Professional . U.S. Food and Drug Administration . 29 June 2020 . 29 June 2020.
  34. Web site: FDA approves combination of pertuzumab, trastuzumab, and hyaluronidase . U.S. Food and Drug Administration (FDA) . 29 June 2020 . 29 June 2020.
  35. Web site: FDA approves daratumumab and hyaluronidase-fihj with pomalidomide and . U.S. Food and Drug Administration (FDA) . 12 July 2021 . 12 July 2021.
  36. Halozyme Announces argenx Receives FDA Approval for Vyvgart Hytrulo With Enhanze for Subcutaneous Use in Generalized Myasthenia Gravis . Halozyme Therapeutics . PR Newswire . 20 June 2023 . 24 June 2023.
  37. 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 . Argenx . 20 June 2023 . 24 June 2023.
  38. Whatcott CJ, Han H, Posner RG, Hostetter G, Von Hoff DD . Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look . Cancer Discovery . 1 . 4 . 291–6 . September 2011 . 22053288 . 3204883 . 10.1158/2159-8290.CD-11-0136 .
  39. Bouga H, Tsouros I, Bounias D, Kyriakopoulou D, Stavropoulos MS, Papageorgakopoulou N, Theocharis DA, Vynios DH . 6 . Involvement of hyaluronidases in colorectal cancer . BMC Cancer . 10 . 1 . 499 . September 2010 . 20849597 . 2949809 . 10.1186/1471-2407-10-499 . Springer Nature . free .
  40. Cheng XB, Sato N, Kohi S, Yamaguchi K . Prognostic impact of hyaluronan and its regulators in pancreatic ductal adenocarcinoma . PLOS ONE . 8 . 11 . e80765 . 2013 . 24244714 . 3823618 . 10.1371/journal.pone.0080765 . 2013PLoSO...880765C . free .
  41. Hautmann SH, Lokeshwar VB, Schroeder GL, Civantos F, Duncan RC, Gnann R, Friedrich MG, Soloway MS . Elevated tissue expression of hyaluronic acid and hyaluronidase validates the HA-HAase urine test for bladder cancer . The Journal of Urology . 165 . 6 Pt 1 . 2068–74 . June 2001 . 11371930 . 10.1016/s0022-5347(05)66296-9 .
  42. Rahmanian M, Heldin P . Testicular hyaluronidase induces tubular structures of endothelial cells grown in three-dimensional collagen gel through a CD44-mediated mechanism . International Journal of Cancer . 97 . 5 . 601–7 . February 2002 . 11807784 . 10.1002/ijc.10087 . 46736648 . free .
  43. Starr CR, Engleberg NC . Role of hyaluronidase in subcutaneous spread and growth of group A streptococcus . Infection and Immunity . 74 . 1 . 40–8 . January 2006 . 16368955 . 1346594 . 10.1128/IAI.74.1.40-48.2006 .
  44. Zukaite V, Biziulevicius GA . Acceleration of hyaluronidase production in the course of batch cultivation of Clostridium perfringens can be achieved with bacteriolytic enzymes . Letters in Applied Microbiology . 30 . 3 . 203–6 . March 2000 . 10747251 . 10.1046/j.1472-765x.2000.00693.x . free .
  45. Isoyama T, Thwaites D, Selzer MG, Carey RI, Barbucci R, Lokeshwar VB . Differential selectivity of hyaluronidase inhibitors toward acidic and basic hyaluronidases . Glycobiology . 16 . 1 . 11–21 . January 2006 . 16166602 . 10.1093/glycob/cwj036 . free .
  46. Book: Principles of anatomy & physiology. Tortora GJ, Derrickson B . 978-1-118-34500-9. 14th. Danvers, MA. 871018672. 2013-12-31. registration.
  47. Anand D, Ray S, Srivastava LM, Bhargava S . Evolution of serum hyaluronan and syndecan levels in prognosis of sepsis patients . Clinical Biochemistry . 49 . 10–11 . 768–776 . July 2016 . 26953518 . 10.1016/j.clinbiochem.2016.02.014 .
  48. Yagmur E, Koch A, Haumann M, Kramann R, Trautwein C, Tacke F . Hyaluronan serum concentrations are elevated in critically ill patients and associated with disease severity . Clinical Biochemistry . 45 . 1–2 . 82–87 . January 2012 . 22085533 . 10.1016/j.clinbiochem.2011.10.016 .
  49. Landsverk SA, Tsai AG, Cabrales P, Intaglietta M . Impact of enzymatic degradation of the endothelial glycocalyx on vascular permeability in an awake hamster model . Critical Care Research and Practice . 2012 . 842545 . 2012 . 22792450 . 3389652 . 10.1155/2012/842545 . free .
  50. Becker BF, Jacob M, Leipert S, Salmon AH, Chappell D . Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases . British Journal of Clinical Pharmacology . 80 . 3 . 389–402 . September 2015 . 25778676 . 4574825 . 10.1111/bcp.12629 .
  51. van der Heijden J, Kolliopoulos C, Skorup P, Sallisalmi M, Heldin P, Hultström M, Tenhunen J . Plasma hyaluronan, hyaluronidase activity and endogenous hyaluronidase inhibition in sepsis: an experimental and clinical cohort study . Intensive Care Medicine Experimental . 9 . 1 . 53 . October 2021 . 34632531 . 8502523 . 10.1186/s40635-021-00418-3 . free .
  52. Baba D, Kashiwabara S, Honda A, Yamagata K, Wu Q, Ikawa M, Okabe M, Baba T . Mouse sperm lacking cell surface hyaluronidase PH-20 can pass through the layer of cumulus cells and fertilize the egg . The Journal of Biological Chemistry . 277 . 33 . 30310–4 . August 2002 . 12065596 . 10.1074/jbc.M204596200 . free .
  53. Book: Alberts, Bruce . vanc . Molecular biology of the cell . Garland Science . New York . 2008 . 1298 . 978-0-8153-4105-5.

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