# US 8,772,246 B2 · Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof

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- Number: US 8,772,246 B2
- Document ID: US8772246B2
- Status: Granted
- Kind: B2
- Application number: 13/694,005
- Filed: 2012-10-18
- Published: 2013-03-07
- Granted: 2014-07-08
- Earliest claimed: 2003-03-05
- Assignees: Halozyme, Inc.
- Applicants: Louis H. Bookbinder; Anirban Kundu; Gregory I. Frost
- Inventors: Louis H. Bookbinder; Anirban Kundu; Gregory I. Frost
- Web page: https://patentgrep.com/patent/US8772246B2

## CPC

- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/24: Antidepressants
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 33/04: Amoebicides
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 9/2474: {Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase}
- C12Y 302/01035: Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 2039/505: {comprising antibodies}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Provided are soluble neutral active Hyaluronidase Glycoproteins (sHASEGP's), methods of manufacture, and their use to facilitate administration of other molecules or to alleviate glycosaminoglycan associated pathologies. Minimally active polypeptide domains of the soluble, neutral active sHASEGP domains are described that include asparagine-linked sugar moieties required for a functional neutral active hyaluronidase domain. Included are modified amino-terminal leader peptides that enhance secretion of sHASEGP. Sialated and pegylated forms of the sHASEGPs also are provided. Methods of treatment by administering sHASEGPs and modified forms thereof also are provided.

## Claims

### Claim 1

A substantially purified hyaluronidase polypeptide, wherein:
the polypeptide contains at least one sugar moiety that is covalently attached to an asparagine residue of the hyaluronidase polypeptide;
the polypeptide is catalytically active;
the polypeptide is secreted; and
the polypeptide consists of a sequence of amino acids that has at least 98% amino acid sequence identity with the sequence of amino acids set forth as amino acid residues 36-483 of SEQ ID NO:1.

### Claim 2 (depends on 1)

The hyaluronidase polypeptide of claim 1 that has at least 99% amino acid sequence identity with the sequence of amino acids set forth as amino acid residues 36-483 of SEQ ID NO:1.

### Claim 3 (depends on 1)

The substantially purified hyaluronidase polypeptide of claim 1 that consists of the sequence of amino acids set forth as amino acids 36-485 of SEQ ID NO:1.

### Claim 4

A substantially purified hyaluronidase polypeptide that consists of the sequence of amino acids set forth as amino acids 36-494 of SEQ ID NO:1, wherein:
the polypeptide contains at least one sugar moiety that is covalently attached to an asparagine residue of the hyaluronidase polypeptide;
the polypeptide is catalytically active; and
the polypeptide is secreted.

### Claim 5 (depends on 1)

The substantially purified hyaluronidase polypeptide of claim 1, wherein the polypeptide is secreted when produced in CHO cells.

### Claim 6 (depends on 1)

The substantially purified hyaluronidase polypeptide of claim 1, wherein the polypeptide is conjugated to a polymer.

### Claim 7 (depends on 6)

The substantially purified hyaluronidase polypeptide of claim 6, wherein the polymer is a polyethylene glycol (PEG) or a dextran.

### Claim 8 (depends on 1)

A pharmaceutical composition, comprising the substantially purified hyaluronidase polypeptide of claim 1.

### Claim 9 (depends on 8)

The pharmaceutical composition of claim 8, further comprising a pharmaceutically active agent.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, wherein the pharmaceutically active agent is a small molecule.

### Claim 11 (depends on 9)

The pharmaceutical composition of claim 9, wherein the pharmaceutically active agent is selected from among a chemotherapeutic agent, an analgesic agent, an anti-inflammatory agent, an antimicrobial agent, an amoebicidal agent, a trichomonocidal agent, an anti-parkinson agent, an anti-malarial agent, an anti-convulsant agent, an anti-depressant agent, and antiarthritics agent, an anti-fungal agent, an antihypertensive agent, an antipyretic agent, an anti-parasite agent, an antihistamine agent, an alpha-adrenargic agonist agent, an alpha blocker agent, an anesthetic agent, a bronchial dilator agent, a biocide agent, a bactericide agent, a bacteriostat agent, a beta adrenergic blocker agent, a calcium channel blocker agent, a cardiovascular drug agent, a contraceptive agent, a decongestant agent, a diuretic agent, a depressant agent, a diagnostic agent, an electrolyte agent, a hypnotic agent, a hormone agent, a hyperglycemic agent, a muscle relaxant agent, a muscle contractant agent, an ophthalmic agent, a parasympathomimetic agent, a sedative agent, a sympathomimetic agent, a tranquilizer agent, a viricide agent, a vitamin agent, a non-steroidal anti-inflammatory agent, an angiotensin converting enzyme inhibitor agent and a sleep inducer.

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, wherein the agent is a toxin or a tumor necrosis factor.

### Claim 13 (depends on 11)

The pharmaceutical composition of claim 11, wherein the agent is an anesthetic agent that is lidocaine or bupivacaine.

### Claim 14 (depends on 9)

The pharmaceutical composition of claim 9, further comprising a hormonal agent.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14, wherein the hormonal agent is epinephrine.

### Claim 16 (depends on 9)

The pharmaceutical composition of claim 9, wherein the pharmaceutically active agent is selected from among an insulin, a cytokine and an antibody.

### Claim 17 (depends on 1)

A conjugate comprising:
the polypeptide of claim 1, a linker and a targeting agent, wherein the linker is attached to the targeting agent, and wherein the linker is attached directly or indirectly to the polypeptide.

### Claim 18 (depends on 6)

A conjugate comprising:
the polypeptide of claim 6, a linker and a targeting agent, wherein the linker is attached to the targeting agent, and wherein the linker is attached directly or indirectly to the polypeptide.

### Claim 19 (depends on 1)

A combination, comprising:
a first composition and a second composition, wherein:
the first composition comprises the hyaluronidase polypeptide of claim 1;
the second composition comprises a pharmaceutically active agent; and
the first and second compositions are separate or combined to form a single composition.

### Claim 20 (depends on 19)

The combination of claim 19 wherein the pharmaceutically active agent is selected from among a small molecule and an antibody.

### Claim 21 (depends on 19)

The combination of claim 19, wherein the pharmaceutically active agent is selected from among a chemotherapeutic agent, an analgesic agent, an anti-inflammatory agent, an antimicrobial agent, an amoebicidal agent, a trichomonocidal agent, an anti-parkinson agent, an anti-malarial agent, an anticonvulsant agent, an anti-depressant agent, and antiarthritics agent, an anti-fungal agent, an antihypertensive agent, an antipyretic agent, an anti-parasite agent, an antihistamine agent, an alpha-adrenargic agonist agent, an alpha blocker agent, an anesthetic agent, a bronchial dilator agent, a biocide agent, a bactericide agent, a bacteriostat agent, a beta adrenergic blocker agent, a calcium channel blocker agent, a cardiovascular drug agent, a contraceptive agent, a decongestant agent, a diuretic agent, a depressant agent, a diagnostic agent, an electrolyte agent, a hypnotic agent, a hormone agent, a hyperglycemic agent, a muscle relaxant agent, a muscle contractant agent, an ophthalmic agent, a parasympathomimetic agent, a sedative agent, a sympathomimetic agent, a tranquilizer agent, a viricide agent, a vitamin agent, a non-steroidal anti-inflammatory agent, an angiotensin converting enzyme inhibitor agent and a sleep inducer.

### Claim 22 (depends on 19)

The combination of claim 19, wherein the pharmaceutically active agent is selected from among insulin, a cytokine and an antibody.

### Claim 23 (depends on 9)

The pharmaceutical composition of claim 9, wherein the pharmaceutically active agent is a monoclonal antibody.

### Claim 24 (depends on 19)

The combination of claim 19, wherein the pharmaceutically active agent is a monoclonal antibody.