Use of endostatin peptides for the treatment of fibrosis

Patent metadata

Field	Value
Publication number	US-9365616-B2
Application number	US-201414207246-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Oct 22, 2009
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

C-terminal endostatin polypeptides are disclosed herein. Polynucleotides encoding these polypeptide, host cells transformed with the polynucleotides, and methods of using these polypeptides and polynucleotides are disclosed. Uses of these polypeptide, polynucleotides and expression vectors include the treatment of fibrosis in a subject. Thus, methods are provided for treating fibrosis, including fibrosis of the skin and/or the lung.

First claim

The invention claimed is:

1. An isolated polypeptide consisting essentially of:
a) the amino acid sequence set forth as amino acids 133-141 of SEQ ID NO: 2;
b) the amino acid sequence set forth as amino acids 145-153 of SEQ ID NO: 2
c) the amino acid sequence set forth as amino acids 145-153 of SEQ ID NO: 13; or
d) the amino acid sequence set forth as amino acids 133-180 of SEQ ID NO: 13; and wherein the polypeptide is amidated.

2. The isolated polypeptide of claim 1 , consisting of:
a) the amino acid sequence set forth as amino acids 133-141 of SEQ ID NO: 2;
b) the amino acid sequence set forth as amino acids 145-153 of SEQ ID NO: 2;
c) the amino acid sequence set forth as amino acids 145-153 of SEQ ID NO: 13; or
d) the amino acid sequence set forth as amino acids 133-180 of SEQ ID NO: 13.

3. The isolated polypeptide of claim 1 , wherein the polypeptide has an amino terminus and a carboxy terminus, and wherein the carboxy terminus of the polypeptide is amidated.

4. A pharmaceutical composition comprising an effective amount of the polypeptide of claim 1 and a pharmaceutically acceptable carrier.

5. A method of treating a subject with fibrosis, comprising
selecting a subject with fibrosis; and
administering to the subject a therapeutically effective amount of the polypeptide of claim 1 ,
thereby treating the subject with fibrosis.

6. The method of claim 5 , wherein the subject has a fibrosis of the skin.

7. The method of claim 5 , wherein the subject has scleroderma, a keloid or hypertrophic scar, idiopathic pulmonary fibrosis, morphea, Graft-Versus-Host Disease, or subepithelial fibrosis.

8. A method for decreasing lysyl oxidase production by a cell, comprising
contacting the cell with an effective amount of the composition of claim 1 , thereby decreasing the production of lysyl oxidase by the cell.

9. A method for increasing the production of matrix metalloprotease by a cell, comprising
contacting the cell with an effective amount of the composition of claim 1 , thereby increasing the production of matrix metalloprotease by the cell.

10. The isolated polypeptide of claim 1 , fused to a heterologous polypeptide.

11. The isolated polypeptide of claim 10 , wherein the heterologous polypeptide aids in detection, purification, stabilization or solubilization.

12. An isolated polypeptide, comprising at least 10 consecutive amino acids and at most 47 amino acids of the amino acid sequence set forth as amino acids 133-180 of SEQ ID NO: 2 or SEQ ID NO: 13, wherein the polypeptide:
a) comprises amino acids 145-153 of SEQ ID NO: 2 or SEQ ID NO: 13;
b) has anti-fibrotic activity; and
c) does not comprise amino acids 1-92 of SEQ ID NO: 2; and
wherein the polypeptide is optionally amidated, and wherein the polypeptide is fused to a heterologous polypeptide by a linker sequence, wherein the linker sequence comprises a thrombin cleavage site and wherein the heterologous polypeptide is an Fc domain.

13. The isolated polypeptide of claim 1 , wherein the polypeptide is benzylated, glycosylated, acetylated, phosphorylated, myristoylated or pegylated.

14. The isolated polypeptide of claim 1 , consisting essentially of the amino acid sequence set forth as amino acids 145-153 of SEQ ID NO: 2 or SEQ ID NO: 13, wherein the polypeptide is amidated.

15. An isolated polypeptide consisting essentially of:
a) the amino acid sequence set forth as amino acids 133-141 of SEQ ID NO: 2 and an Fc domain;
b) the amino acid sequence set forth as amino acids 145-153 of SEQ ID NO: 2 and an Fc domain;
c) the amino acid sequence set forth as amino acids 145-153 of SEQ ID NO: 13 and an Fc domain; or
d) the amino acid sequence set forth as amino acids 133-180 of SEQ ID NO: 13 and an Fc domain.

16. A method of treating a subject with fibrosis, comprising
selecting a subject with fibrosis; and
administering to the subject a therapeutically effective amount of the polypeptide of claim 15 ,
thereby treating the subject with fibrosis.

17. A method of treating a subject with fibrosis, comprising
selecting a subject with fibrosis; and
administering to the subject a therapeutically effective amount of the polypeptide of claim 2 ,
thereby treating the subject with fibrosis.

18. The method of claim 16 , wherein the subject has a fibrosis of the skin.

19. The method of claim 16 , wherein the subject has scleroderma, a keloid or hypertrophic scar, idiopathic pulmonary fibrosis, morphea, Graft-Versus-Host Disease, or subepithelial fibrosis.

20. A pharmaceutical composition comprising an effective amount of the polypeptide of claim 15 and a pharmaceutically acceptable carrier.

Assignees

• Univ Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Feghali-Bostwick Carol A
• Yamaguchi Yukie

Classifications

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• C07K14/47

  from mammals · CPC title

• C07K14/78

  Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG] · CPC title