Hyaluronidase
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EC no.3.2.1.35
CAS no.37326-33-3
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Hyaluronidase
Identifiers
SymbolHyaluronidase_1
PfamPF07212
InterProIPR009860
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PDBsumstructure summary
Hyaluronidase
Identifiers
SymbolHyaluronidase_2
PfamPF07555
InterProIPR011496
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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.[3] 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 (EC 3.2.1.35), i.e. they cleave the (1→4)-linkages between N-acetylglucosamine and glucuronate. The term hyaluronidase may also refer to hyaluronoglucuronidases (EC 3.2.1.36), which cleave (1→3)-linkages. In addition, bacterial hyaluronate lyases (EC 4.2.2.1) may also be referred to as hyaluronidases, although this is uncommon.[6]

Use as a drug

Hyaluronidase
Clinical data
Pronunciation/haɪ(ə)ljuˌrɑːnɪˈdeɪs/[7]
Trade namesHylenex, HyQvia, Vitrase, others
Other nameshyaluronidase-fihj, hyaluronidase-oysk, hyaluronidase-zzxf
AHFS/Drugs.comMicromedex Detailed Consumer Information
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Pregnancy
category
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
Identifiers
  • hyaluronidase
CAS Number
DrugBank
ChemSpider
  • none
UNII
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ChEMBL
Chemical and physical data
FormulaC2455H3775N617O704S21
Molar mass53871.08 g·mol−1
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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.[26] 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.[23]
  • Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed or are contra‑indicated.[23]
  • Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma (MM) patients.[23]
  • Hypogammaglobulinaemia in patients pre‑ and post‑allogeneic hematopoietic stem cell transplantation.[23]

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.[5]

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]

References

  1. ↑ Meyer K (1971). "Hyaluronidases". In Boyer PD (ed.). Enzymes. Vol. V. New York: Academic Press. pp. 307–320. ISBN 978-0-12-122705-0.
  2. ↑ Stern R, Kogan G, Jedrzejas MJ, Soltés L (November 2007). "The many ways to cleave hyaluronan". Biotechnology Advances. 25 (6): 537–57. doi:10.1016/j.biotechadv.2007.07.001. PMID 17716848.
  3. 1 2 Csóka AB, Scherer SW, Stern R (September 1999). "Expression analysis of six paralogous human hyaluronidase genes clustered on chromosomes 3p21 and 7q31". Genomics. 60 (3): 356–61. doi:10.1006/geno.1999.5876. PMID 10493834.
  4. ↑ Csoka AB, Frost GI, Stern R (December 2001). "The six hyaluronidase-like genes in the human and mouse genomes". Matrix Biology. 20 (8): 499–508. doi:10.1016/S0945-053X(01)00172-X. PMID 11731267.
  5. 1 2 Chanmee T, Ontong P, Itano N (May 2016). "Hyaluronan: A modulator of the tumor microenvironment". Cancer Letters. 375 (1): 20–30. doi:10.1016/j.canlet.2016.02.031. PMID 26921785.
  6. ↑ "Hyaluronidase". ENZYME. ExPASy. Retrieved 17 November 2016.
  7. ↑ "hyaluronidase". Merriam-Webster.com Dictionary. Retrieved 2020-07-03.
  8. ↑ "Hyaluronidase Use During Pregnancy". Drugs.com. 14 June 2019. Retrieved 3 February 2020.
  9. ↑ "ARTG ID 27749 Hyalase 1500IU powder for injection ampoule". Therapeutic Goods Administration (TGA). Archived from the original on 29 October 2021. Retrieved 9 August 2020.
  10. ↑ "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. Retrieved 1 May 2020.
  11. ↑ "HyQvia 100 mg/ml solution for infusion for subcutaneous use - Summary of Product Characteristics (SmPC)". (emc). 15 January 2020. Retrieved 1 May 2020.
  12. ↑ "Chemotherapy extravasation guideline" (PDF). WOSCAN Cancer Nursing and Pharmacy Group. September 2009. Archived from the original (PDF) on 27 January 2018. Retrieved 4 June 2017.
  13. ↑ Borzabadi-Farahani A, Mosahebi A, Zargaran D (2022). "A Scoping Review of Hyaluronidase Use in Managing the Complications of Aesthetic Interventions". Aesthetic Plastic Surgery. doi:10.1007/s00266-022-03207-9. PMID 36536092.
  14. ↑ "Vitrase-hyaluronidase, ovine injection, solution". DailyMed. 29 May 2018. Retrieved 1 May 2020.
  15. ↑ "Amphadase- hyaluronidase injection". DailyMed. 28 November 2016. Retrieved 1 May 2020.
  16. ↑ "Hydase- hyaluronidase injection, solution". DailyMed. 16 November 2015. Retrieved 1 May 2020.
  17. ↑ "Drug Approval Package: Vitrase (Hyaluronidase) NDA #021640". U.S. Food and Drug Administration (FDA). 15 November 2004. Retrieved 1 May 2020.
  18. ↑ "Drug Approval Package: Amphadase (Hyaluronidase) NDA #021665". U.S. Food and Drug Administration (FDA). 4 February 2005. Retrieved 1 May 2020.
  19. ↑ "Hydase: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). 23 March 2020. Retrieved 1 May 2020.
  20. ↑ "Drug Approval Package: Hylenex Recombinant (Hyaluronidase) NDA #021859". U.S. Food and Drug Administration (FDA). 3 January 2006. Retrieved 1 May 2020.
  21. ↑ "Halozyme Therapeutics and Baxter Healthcare Corporation Announce FDA Approval of Hylenex". Archived from the original on October 18, 2007. Retrieved 2008-11-07.
  22. ↑ "Hylenex recombinant (hyaluronidase- human recombinant injection), solution". DailyMed. 1 January 2016. Retrieved 1 May 2020.
  23. 1 2 3 4 5 "HyQvia EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 1 May 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  24. ↑ "Hyqvia". U.S. Food and Drug Administration (FDA). 27 February 2015. Archived from the original on 22 July 2017. Retrieved 1 May 2020.
  25. ↑ "Hyqvia Approval Letter". U.S. Food and Drug Administration (FDA). Archived from the original on 22 July 2017. Retrieved 20 November 2015.
  26. 1 2 "Hyqvia (immune globulin 10 percent- human with recombinant human hyaluronidase) kit". DailyMed. Retrieved 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. doi:10.1007/s40259-014-0104-3. PMID 24925799. S2CID 8091134.
  28. ↑ "Drug Approval Package: Rituxan Hycela". U.S. Food and Drug Administration (FDA). 11 October 2018. Retrieved 1 May 2020.
  29. ↑ "Rituxan Hycela- rituximab and hyaluronidase injection, solution". DailyMed. 3 December 2019. Retrieved 1 May 2020.
  30. ↑ "Drug Approval Package: Herceptin Hylecta". U.S. Food and Drug Administration (FDA). 17 October 2019. Retrieved 1 May 2020.
  31. ↑ "Herceptin Hylecta- trastuzumab and hyaluronidase-oysk injection, solution". DailyMed. 13 May 2019. Retrieved 1 May 2020.
  32. ↑ "Darzalex Faspro: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 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 (Press release). 29 June 2020. Retrieved 29 June 2020.
  34. ↑ "FDA approves combination of pertuzumab, trastuzumab, and hyaluronidase". U.S. Food and Drug Administration (FDA). 29 June 2020. Retrieved 29 June 2020.
  35. ↑ "FDA approves daratumumab and hyaluronidase-fihj with pomalidomide and". U.S. Food and Drug Administration (FDA). 12 July 2021. Retrieved 12 July 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  36. ↑ "Halozyme Announces argenx Receives FDA Approval for Vyvgart Hytrulo With Enhanze for Subcutaneous Use in Generalized Myasthenia Gravis" (Press release). Halozyme Therapeutics. 20 June 2023. Retrieved 24 June 2023 – via PR Newswire.
  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 (Press release). 20 June 2023. Retrieved 24 June 2023.
  38. ↑ Whatcott CJ, Han H, Posner RG, Hostetter G, Von Hoff DD (September 2011). "Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look". Cancer Discovery. 1 (4): 291–6. doi:10.1158/2159-8290.CD-11-0136. PMC 3204883. PMID 22053288.
  39. ↑ Bouga H, Tsouros I, Bounias D, Kyriakopoulou D, Stavropoulos MS, Papageorgakopoulou N, et al. (September 2010). "Involvement of hyaluronidases in colorectal cancer". BMC Cancer. Springer Nature. 10 (1): 499. doi:10.1186/1471-2407-10-499. PMC 2949809. PMID 20849597.
  40. ↑ Cheng XB, Sato N, Kohi S, Yamaguchi K (2013). "Prognostic impact of hyaluronan and its regulators in pancreatic ductal adenocarcinoma". PLOS ONE. 8 (11): e80765. Bibcode:2013PLoSO...880765C. doi:10.1371/journal.pone.0080765. PMC 3823618. PMID 24244714.
  41. ↑ Hautmann SH, Lokeshwar VB, Schroeder GL, Civantos F, Duncan RC, Gnann R, Friedrich MG, Soloway MS (June 2001). "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. doi:10.1016/s0022-5347(05)66296-9. PMID 11371930.
  42. ↑ Rahmanian M, Heldin P (February 2002). "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. doi:10.1002/ijc.10087. PMID 11807784. S2CID 46736648.
  43. ↑ Starr CR, Engleberg NC (January 2006). "Role of hyaluronidase in subcutaneous spread and growth of group A streptococcus". Infection and Immunity. 74 (1): 40–8. doi:10.1128/IAI.74.1.40-48.2006. PMC 1346594. PMID 16368955.
  44. ↑ Zukaite V, Biziulevicius GA (March 2000). "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. doi:10.1046/j.1472-765x.2000.00693.x. PMID 10747251.
  45. ↑ Isoyama T, Thwaites D, Selzer MG, Carey RI, Barbucci R, Lokeshwar VB (January 2006). "Differential selectivity of hyaluronidase inhibitors toward acidic and basic hyaluronidases". Glycobiology. 16 (1): 11–21. doi:10.1093/glycob/cwj036. PMID 16166602.
  46. ↑ Tortora GJ, Derrickson B (2013-12-31). Principles of anatomy & physiology (14th ed.). Danvers, MA. ISBN 978-1-118-34500-9. OCLC 871018672.{{cite book}}: CS1 maint: location missing publisher (link)
  47. ↑ Anand D, Ray S, Srivastava LM, Bhargava S (July 2016). "Evolution of serum hyaluronan and syndecan levels in prognosis of sepsis patients". Clinical Biochemistry. 49 (10–11): 768–776. doi:10.1016/j.clinbiochem.2016.02.014. PMID 26953518.
  48. ↑ Yagmur E, Koch A, Haumann M, Kramann R, Trautwein C, Tacke F (January 2012). "Hyaluronan serum concentrations are elevated in critically ill patients and associated with disease severity". Clinical Biochemistry. 45 (1–2): 82–87. doi:10.1016/j.clinbiochem.2011.10.016. PMID 22085533.
  49. ↑ Landsverk SA, Tsai AG, Cabrales P, Intaglietta M (2012). "Impact of enzymatic degradation of the endothelial glycocalyx on vascular permeability in an awake hamster model". Critical Care Research and Practice. 2012: 842545. doi:10.1155/2012/842545. PMC 3389652. PMID 22792450.
  50. ↑ Becker BF, Jacob M, Leipert S, Salmon AH, Chappell D (September 2015). "Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases". British Journal of Clinical Pharmacology. 80 (3): 389–402. doi:10.1111/bcp.12629. PMC 4574825. PMID 25778676.
  51. ↑ van der Heijden J, Kolliopoulos C, Skorup P, Sallisalmi M, Heldin P, Hultström M, Tenhunen J (October 2021). "Plasma hyaluronan, hyaluronidase activity and endogenous hyaluronidase inhibition in sepsis: an experimental and clinical cohort study". Intensive Care Medicine Experimental. 9 (1): 53. doi:10.1186/s40635-021-00418-3. PMC 8502523. PMID 34632531.
  52. ↑ Baba D, Kashiwabara S, Honda A, Yamagata K, Wu Q, Ikawa M, Okabe M, Baba T (August 2002). "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. doi:10.1074/jbc.M204596200. PMID 12065596.
  53. ↑ Alberts B (2008). Molecular biology of the cell. New York: Garland Science. p. 1298. ISBN 978-0-8153-4105-5.
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