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Hyaluronidases are a family of 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. (1971). 9780121227050, Academic Press. ISBN 9780121227050 The three main types of hyaluronidases are two classes of eukaryotic endoglycosidase hydrolases and a prokaryotic lyase-type of glycosidase.
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). 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. 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-; this generates hyaluronic acid oligosaccharides.
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.
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), Amphadase (bovine, October 2004) and Hydase (bovine, October 2005).
Human recombinant hyaluronidase (Hylenex Recombinant)—approved for use in the United States in December 2005—corresponds to the soluble fragment of human HYAL5 (PH20) produced in cell culture by genetically engineered Chinese hamster ovary cells containing a DNA plasmid encoding the enzyme.
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.
Hyaluronidase is available in some Combination drug drug products in the United States: rituximab/hyaluronidase (Rituxan Hycela), trastuzumab/hyaluronidase-oysk (Herceptin Hylecta), daratumumab/hyaluronidase-fihj (Darzalex Faspro), pertuzumab/trastuzumab/hyaluronidase–zzxf (Phesgo).
In July 2021, the US 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.
Efgartigimod alfa/hyaluronidase (Vyvgart Hytrulo) was approved for the treatment of generalized myasthenia gravis in the United States in June 2023.
Ocrelizumab/hyaluronidase (Ocrevus Zunovo) was approved for medical use in the United States in September 2024.
Atezolizumab/hyaluronidase (Tecentriq Hybreza) was approved for medical use in the United States in September 2024.
Nivolumab/hyaluronidase (Opdivo Qvantig) was approved for medical use in the United States in December 2024.
In October 2025, the US Food and Drug Administration approved a combination of atezolizumab, hyaluronidase, and lurbinectedin for the treatment of adults with extensive-stage small cell lung cancer.
Elevated tissue expression of hyaluronic acid and hyaluronidase validates the hyaluronic acid-hyaluronidases urine test for bladder cancer. 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 (e.g., apigenin and 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.
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.
Mammalian ova are covered in a layer of intertwined in an extracellular matrix that contains a high concentration of hyaluronan. When a capacitation 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.
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