Ligand for vascular endothelial growth factor receptor

• US 20020058619A1
• Filed: 02/02/2001
• Published: 05/16/2002
• Est. Priority Date: 02/04/2000
• Status: Active Grant

• Current Assignee: International Business Machines Corporation, Supratek Pharma, Inc.
• Original Assignee: Supratek Pharma, Inc.
• Inventors: Alakhov, Valery, Tchistiakova, Lioudmila, Pietrzynski, Grzegorz, Li, Shengmin
• Granted Patent: US 6,733,755 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• 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: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/52 Cytokines; Lymphokines; Interferons
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

The present invention relates to compositions comprised of a peptide ligand or derivatives thereof that are capable of specific binding to the high affinity receptor-1 of vascular endothelial growth factor (VEGF) and structure similar receptors. The invention further provides a peptide ligand or derivatives thereof that are capable of inhibiting angiogenesis induced by VEGF. The present invention also provides a method for treatment or diagnosis of disease associated with angiogenesis in a patient in need of therapy comprising administering to the patient an effective amount of the pharmaceutical composition of the present invention and a pharmaceutical acceptable carrier.

Claims

1. A pharmaceutical composition comprising at least one peptide or derivative thereof, wherein said polypeptide or derivative thereof is capable of specific binding with the high affinity VEGF receptor-1 or a derivative of the VEGF receptor-1 and structural similar receptors.

2. A pharmaceutical composition according to claim 1 wherein said polypeptide or derivative thereof comprises the following motif of SEQ. ID. NO.:

. 8;

Y₁-X-X-Y₂-Y₃-Y₄-X-X-X-Y₅-X-X-X-X-X-Y₆, where

Y₁ is Asn or Gln

Y₂ is negatively charged amino acid comprising of Glu or Asp

Y₃ is Ile, Leu, Val or Met

Y₄ is negatively charged amino acid comprising of Glu or Asp

Y₅ is aromatic amino acid comprising of Trp, Phe, Tyr or His

Y₆ is aromatic amino acid comprising of Tyr, Tip, Phe or His

X is any amino acid,

or a substitution variant, addition variant or other chemical derivative thereof.

3. A pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof comprises the amino acid sequence of SEQ. ID. NO.:

1.

4. A pharmaceutical composition according to claim 3, wherein derivatives of said SEQ. ID. NO.:

1 comprises oligopeptides, chemical derivatives or peptidomimetic that are capable of specific binding with the high affinity VEGF receptor-1 or a derivative of the VEGF receptor-1.

5. A pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof comprises t he amino acid sequence of SEQ. ID. NO.:

2.

6. A pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof comprises the amino acid sequence of SEQ. ID. NO.:

3.

7. A pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof comprises the amino acid sequence of SEQ. ID. NO.:

4.

8. A pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof comprises the amino acid sequence of SEQ. ID. NO.:

5.

9. A pharmaceutical composition according to claim 1, wherein said peptide or derivative thereof comprises the amino acid sequence of SEQ. ID. NO.:

7.

10. The pharmaceutical composition according to the claim 1, where said polypeptide or derivative thereof modulates the interaction of VEGF with its high affinity VEGF receptor and modulates biological effects mediated by binding.

11. The pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof comprises at least about 20% of the biological activity of the peptide or derivative thereof said SEQ. ID. NO.:

3 and binding activity such that said peptide or derivative thereof competes with the labeled peptide in SEQ. ID. NO.;

4 for binding to the VEGF receptor-1.

12. The pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof comprises at least about 20% of the biological activity of the polypeptide or derivative thereof said SEQ. ID. NO.:

3.

13. The pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof comprises binding activity such that said polypeptide or derivative thereof competes with the labeled polypeptide in SEQ. ID. NO.:

4 for binding to the VEGF receptor-1.

14. The pharmaceutical composition according to claim 11, wherein said biological activity is measured using in vitro bioassays comprising VEGF receptor-1 binding assay, endothelial tube formation on Matrigel.RTM., or endothelial cell mitogenic assay.

15. The pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof further comprises a biological agent.

16. The pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof further comprises a carrier.

17. The pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof further comprises a biological agent and a carrier.

18. The pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof further comprises a modified biological agent.

19. The pharmaceutical composition according to claim 1, wherein said polypeptide or derivative thereof further comprises a therapeutic agent.

20. A method of treating a disease associated with angiogenesis in a patient in need of such therapy comprising administering to said patient an effective amount of said pharmaceutical composition of claim 1 and a pharmaceutical acceptable carrier.

21. An isolated nucleic acid encoding the polypeptide or derivatives thereof comprising amino acid sequences of SEQ. ID. NOs.:

1, 2, 3, 4, 5, 7 or 8.

22. An expression vector comprising the nucleic acid sequences of claim 21.

23. A host cell transfected with the expression vector of claim 22.

24. A composition comprising a nucleic acid molecule and carrier, wherein the nucleic acid molecule encodes a polypeptide encoding the amino acid sequence of SEQ. ID. NOs.:

1, 2, 3, 4, 5, 7 or 8.