Disintegrin variants and pharmaceutical uses thereof

Patent metadata

Field	Value
Publication number	US-10508137-B2
Application number	US-201515505357-A
Country	US
Kind code	B2
Filing date	Aug 21, 2015
Priority date	Aug 22, 2014
Publication date	Dec 17, 2019
Grant date	Dec 17, 2019

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.

First claim

What is claimed is:

1. A disintegrin variant of rhodostomin comprising the amino acid sequence of SEQ ID NO: 1, comprising:
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.

2. The disintegrin variant of claim 1 , comprising the mutant RGD loop, the mutant linker and the mutant C-terminus.

3. A disintegrin variant comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 123, 124, 147, 149 and 171.

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

5. A pharmaceutical composition comprising the disintegrin variant of claim 1 and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising the disintegrin variant of claim 3 and a pharmaceutically acceptable carrier.

7. The disintegrin variant of claim 1 , comprising a mutant RGD loop of SEQ ID NO: 331 and a mutant linker of SEQ ID NO: 313.

8. A disintegrin variant comprising 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.

9. A pharmaceutical composition comprising the disintegrin variant of claim 8 and a pharmaceutically acceptable carrier.

Assignees

• Univ Nat Cheng Kung
• Nat Cheng Kung Univeristy

Inventors

• Chuang Woei-Jer

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P35/00

  Antineoplastic agents · CPC title