Novel antiangiogenic peptides

• US 20060099684A1
• Filed: 10/31/2005
• Published: 05/11/2006
• Est. Priority Date: 04/29/2003
• Status: Active Grant

• Current Assignee: Children's Medical Center Corporation
• Original Assignee: Children's Medical Center Corporation
• Inventors: Moses, Marsha A., Fernandez, Cecilia A.
• Granted Patent: US 7,371,812 B2
• Time in Patent Office: Days
• US Class Current: 435/69.1
• CPC Class Codes: 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
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 14/8146 Metalloprotease (E.C. 3.4.24) inhibitors, e.g. tissue inhibitor of metallo proteinase, TIMP

Abstract

The present invention provides an antiangiogenic polypeptide having the amino acid sequence set forth in SEQ ID NO: 1, or a fragment thereof, which is effective to inhibit endothelial cell proliferation as determined by the capillary EC proliferation assay. Preferably, the fragment has at least 50% inhibition of bFGF-stimulated EC proliferation at 5 μg/ml-20 μg/ml, more preferably 75% inhibition, most preferably 95% inhibition.

Claims

1. An antiangiogenic polypeptide having the amino acid sequence set forth in SEQ ID NO:

1, a fragment thereof having endothelial cell inhibitory activity, or a polypeptide having greater than 80% identity with SEQ ID NO;

1.

2. An isolated polynucleotide encoding the antiangiogenic polypeptide of claim 1.

3. A vector comprising the polynucleotide of claim 2.

4. A pharmaceutical composition comprising an antiangiogenic polypeptide of claim 1, or a nucleic acid encoding such a polypeptide, in a therapeutically effective amount capable of inhibiting endothelial cell proliferation.

5. A method of inhibiting angiogenesis in a subject having an angiogenic disease or disorder, or at risk for developing an angiogenic disease or disorder, which comprises administering to the subject of pharmaceutical composition of claim 4.

6. The method of claim 5, wherein the angiogenesis disease or disorder is restenosis.

7. The method of claim 5, wherein the angiogenesis disease or disorder is cancer.

8. The method of claim 7, wherein the cancer is a solid tumor.

9. The method of claim 7, wherein the cancer is medullary thyroid cancer.

10. The method of claim 7, wherein the tumor is a tumor of the central nervous system.

11. The method according to claim 5, wherein the angiogenesis disease or disorder is an ophthalmologic disease or disorder.

12. The method of claim 11, wherein the ophthalmologic disease or disorder is retinopathy, diabetic retinopathy or macular degeneration.

14. A method of treating a subject having a tissue remodeling-associated condition, or at risk of having a tissue remodeling-associated condition, comprising administering to the subject of pharmaceutical composition of claim 4.

15. The method of claim 14, wherein the tissue remodeling-associated condition is arthritis or rheumatoid arthritis.

16. The method of claim 5, wherein said administering is conducted in conjunction with other known angiogenesis inhibitors.

17. The method of claim 5, wherein said administering comprises intravenous, transdermal, intrasynovial, intramuscular, or oral administration.

18. The method of claim 5, wherein said administering comprises administering a gene therapy vector that constitutively expresses the antiangiogenic polypeptide of claim 1.

19. The method of claim 5, wherein said administering comprises prophylactic administration.

20. The method of claim 5, wherein said administering comprises therapeutic administration.

21. The method of claim 5, wherein said risk for developing an angiogenic disease or disorder is determined genetically.

22. The method of claim 5, wherein said risk for developing an angiogenic disease or disorder is determined by measuring levels of cancer marker protein.

23. The method of claim 22, wherein the cancer marker protein is selected from the group consisting of calcitonin, PSA, thymosin β

-15, thymosin β

-16, or matrix metalloproteinase (MMP).

24. The method of claim 14, wherein said risk for developing a tissue remodeling associated condition is determined genetically.

13. The method of 5, wherein said administering is conducted in conjunction with chemotherapy.

25. An article of manufacture comprising packaging material and a pharmaceutical composition contained within said packaging material, wherein said pharmaceutical composition is capable of inhibiting angiogenesis in a tissue associated with a disease condition, wherein said packaging material comprises a label which indicates that said pharmaceutical composition can be used for treating disease conditions by inhibiting angiogenesis, and wherein said pharmaceutical composition comprises a antiangiogenic polypeptide having the amino acid sequence set forth in SEQ ID NO:

1, a fragment thereof having endothelial cell inhibitory activity, or a polypeptide having greater than 80% identity with SEQ ID NO;

1, or a nucleic acid encoding the polypeptide, in a therapeutically effective amount capable of inhibiting endothelial cell proliferation.