# US 10,870,684 B2 · Disintegrin variants and pharmaceutical uses thereof

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- Number: US 10,870,684 B2
- Document ID: US10870684B2
- Status: Granted
- Kind: B2
- Application number: 16/556,952
- Filed: 2019-08-30
- Published: 2020-01-09
- Granted: 2020-12-22
- Earliest claimed: 2014-08-22
- Assignees: National Cheng Kung University
- Applicants: National Cheng Kung University
- Inventors: Woei-Jer Chuang
- Web page: https://patentgrep.com/patent/US10870684B2

## CPC

- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- C07K 14/46: from vertebrates
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 27/10: for accommodation disorders, e.g. myopia
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2848: {against integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61}
- C12N 9/6418: {from snakes}
- 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)
- C07K 16/2839: {against the integrin superfamily}
- C07K 16/2842: {against integrin beta1-subunit-containing molecules, e.g. CD29, CD49}
- C07K 2318/20: Antigen-binding scaffold molecules wherein the scaffold is not an immunoglobulin variable region or antibody mimetics
- C12N 15/09: Recombinant DNA-technology
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)

## Abstract

Disintegrin variants that bind specifically to one or more of α5β1 and αv integrins, such as αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8, but with reduced binding activity to αIIbβ3, are described. Also described are uses of the disintegrin variants for the treatment or prevention of a disease associated with an αv integrin or an α5β1 integrin.

## Claims

### Claim 1

A polynucleotide encoding a disintegrin variant of rhodostomin comprising the amino acid sequence of SEQ ID NO: 1, wherein the disintegrin variant comprises:
a mutant RGD loop, wherein the amino acid sequence at positions 46 to 53 of SEQ ID NO: 1 is substituted with an amino acid sequence selected from the group consisting of SEQ ID NOs: 329, 330, 331, 353, and 354, and
at least one selected from the group consisting of:
(a) a mutant linker, wherein the amino acid sequence at positions 39 to 45 of SEQ ID NO: 1 is substituted with an amino acid sequence selected from the group consisting of SEQ ID NO: 306 to SEQ ID NO: 318; and
(b) a mutant C-terminus, wherein the amino acid sequence at positions 65 to 68 of SEQ ID NO: 1 is substituted with an amino acid sequence selected from the group consisting of SEQ ID NOs: 319, 323, 324, 326, 327, 328, 337, and 352,
wherein the disintegrin variant has an increased selectivity for at least one of αvβ1, αvβ3, αvβ5, αvβ6, αvβ8 and α5β1 integrins over αIIbβ3 integrin as compared to wild-type rhodostomin having the amino acid sequence of SEQ ID NO: 1.

### Claim 2 (depends on 1)

The polynucleotide of claim 1, wherein the disintegrin variant comprises the mutant RGD loop, the mutant linker and the mutant C-terminus.

### Claim 3 (depends on 1)

The polynucleotide of claim 1, wherein the disintegrin variant comprises a mutant RGD loop of SEQ ID NO: 331 and a mutant linker of SEQ ID NO: 313.

### Claim 4 (depends on 1)

The polynucleotide of claim 1, wherein the disintegrin variant comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 120, 121, 123, 124, 129-144, 147, 149, 160, 166, 169, 171, 339, 347, and 349.

### Claim 5 (depends on 1)

The polynucleotide of claim 1, wherein the disintegrin variant comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 123, 124, 147, 149 and 171.

### Claim 6 (depends on 1)

The polynucleotide of claim 1, wherein the disintegrin variant is conjugated with albumin or Fc.

### Claim 7 (depends on 1)

A recombinant host cell comprising the polynucleotide of claim 1.

### Claim 8 (depends on 1)

The polynucleotide of claim 1, wherein the disintegrin variant is further pegylated.