Antibodies to VEGF-C
View Patent ↗Provided are purified and isolated VEGF-C polypeptides capable of binding to at least one of KDR receptor tyrosine kinase (VEGFR-2) and Flt4 receptor tyrosine kinase (VEGFR-3); analogs of such peptides that have VEGF-C-like or VEGF-like biological activities or that are VEGF or VEGF-C inhibitors; polynucleotides encoding the polypeptides; vectors and host cells that embody the polynucleotides; pharmaceutical compositions and diagnostic reagents comprising the polypeptides; and methods of making and using the polypeptides.
1. An antibody that specifically binds to a polypeptide that binds and stimulates phosphorylation of Flt4 receptor tyrosine kinase (Flt4), wherein the polypeptide has an amino acid sequence consisting of a portion of amino acids 103 to 282 of SEQ ID NO: 8, said polypeptide lacking all of amino acids of SEQ ID NO: 8 beyond position 282.
2. An antibody according to claim 1 , wherein amino-terminal amino acids 2 through 18 of said polypeptide correspond to amino acids 2 through 18 set forth in SEQ ID NO: 5.
3. An antibody according to claim 1 that inhibits binding between the polypeptide and Flt4.
4. An antibody according to claim 3 , wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody inhibits binding between the polypeptide and VEGFR-2.
5. An antibody according to claim 1 , wherein the antibody inhibits the polypeptide from stimulating phosphorylation of Flt4.
6. An antibody according to claim 5 that is a monoclonal antibody.
7. An antibody according to claim 5 , wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody inhibits the polypeptide from stimulating phosphorylation of VEGFR-2.
8. An antibody according to claim 7 that is a monoclonal antibody.
9. An antibody that specifically binds to a polypeptide that binds and stimulates phosphorylation of Flt4 receptor tyrosine kinase (Flt4), wherein the polypeptide comprises a portion of SEQ ID NO: 8 effective to permit such binding, and wherein the polypeptide has an apparent molecular weight of approximately 23 kD as assessed by SDS-PAGE under reducing conditions.
10. An antibody according to claim 9 , wherein amino-terminal amino acids 2 through 18 of said polypeptide correspond to amino acids 2 through 18 set forth in SEQ ID NO: 5.
11. An antibody according to claim 10 that inhibits binding between the polypeptide and Flt4.
12. An antibody according to claim 11 , wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody inhibits binding between the polypeptide and VEGFR-2.
13. An antibody according to claim 9 , wherein the antibody inhibits the polypeptide from stimulating phosphorylation of Flt4.
14. An antibody according to claim 13 that is a monoclonal antibody.
15. An antibody according to claim 13 , wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody inhibits the polypeptide from stimulating phosphorylation of VEGFR-2.
16. An antibody according to claim 15 that is a monoclonal antibody.
17. A composition comprising an antibody according to any one of claims 1 - 16 in a pharmaceutically acceptable carrier.
18. An antibody that specifically binds with a soluble polypeptide ligand of Flt4 receptor tyrosine kinase, wherein the soluble polypeptide ligand comprises a polypeptide encoded by the cDNA insert of plasmid pFlt4-L, having ATCC Accession No. 97231; wherein the polypeptide has a molecular weight of about 23 kD as assessed by SDS-PAGE under reducing conditions; and wherein binding of the antibody to the polypeptide ligand blocks activation of Flt-4 receptor tyrosine kinase by the polypeptide ligand.
19. An antibody according to claim 18 , wherein amino-terminal amino acids 2 through 18 of said polypeptide correspond to amino acids 2 through 18 set forth in SEQ ID NO: 5.
20. An antibody according to claim 18 that inhibits binding between the polypeptide and Flt4.
21. An antibody according to claim 20 , wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody inhibits binding between the polypeptide and VEGFR-2.
22. An antibody according to claim 18 , wherein the antibody inhibits the polypeptide from stimulating phosphorylation of Flt4.
23. An antibody according to claim 22 that is a monoclonal antibody.
24. An antibody according to claim 22 , wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody inhibits the polypeptide from stimulating phosphorylation of VEGFR-2.
25. An antibody according to claim 24 that is a monoclonal antibody.
26. A molecule that comprises an antigen-binding fragment of an antibody that specifically binds to a polypeptide that binds and stimulates phosphorylation of Flt4 receptor tyrosine kinase (Flt4), wherein the polypeptide has an amino acid sequence consisting of a portion of amino acids 103 to 282 of SEQ ID NO:8, said polypeptide lacking all of amino acids of SEQ ID NO:8 beyond position 282; wherein the molecule specifically binds the polypeptide.
27. The molecule of claim 26 , wherein the antibody inhibits binding between the polypeptide and Flt4.
28. The molecule of claim 26 , wherein the antibody is a monoclonal antibody that inhibits the polypeptide from stimulating phosphorylation of Flt4.
29. The molecule of claim 26 , wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody is a monoclonal antibody that inhibits the polypeptide from stimulating phosphorylation of VEGFR-2 and inhibits the polypeptide from stimulating phosphorylation of Flt4.
30. An antibody substance selected from the group consisting of:
(a) an antibody that specifically binds a VEGF-C polypeptide that consists of amino acids 103 to 227 of SEQ ID NO: 8, and
(b) a polypeptide comprising a fragment of (a) that specifically binds to said VEGF-C polypeptide;
wherein the antibody substance inhibits the VEGF-C polypeptide from stimulating phosphorylation of VEGFR-2; and wherein the antibody substance inhibits the VEGF-C polypeptide from stimulating phosphorylation of VEGFR-3.
31. An antibody that specifically binds to a polypeptide that binds and stimulates phosphorylation of Flt4 receptor tyrosine kinase (Flt4), wherein the polypeptide has an amino acid sequence consisting of a portion of amino acids 103 to 282 of SEQ ID NO: 8, said polypeptide lacking all of amino acids of SEQ ID NO: 8 beyond position 282, wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody inhibits binding between the polypeptide and VEGFR-2.
32. An antibody that specifically binds to a polypeptide that binds and stimulates phosphorylation of Flt4 receptor tyrosine kinase (Flt4), wherein the polypeptide comprises a portion of SEQ ID NO: 8 effective to permit such binding, wherein the polypeptide has an apparent molecular weight of approximately 23 kD as assessed by SDS-PAGE under reducing conditions, wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody inhibits binding between the polypeptide and VEGFR-2.
33. An antibody that specifically binds with a soluble polypeptide ligand of Flt4 receptor tyrosine kinase, wherein the soluble polypeptide ligand comprises a polypeptide encoded by the cDNA insert of plasmid pFlt4-L, having ATCC Accession No. 97231; wherein the polypeptide has an apparent molecular weight of approximately 23 kD as assessed by SDS-PAGE under reducing conditions, wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody inhibits binding between the polypeptide and VEGFR-2.
34. A molecule that comprises an antigen-binding fragment of an antibody that specifically binds to a polypeptide that binds and stimulates phosphorylation of Flt4 receptor tyrosine kinase (Flt4), wherein the polypeptide comprises a portion of SEQ ID NO: 8 effective to permit such binding, and wherein the polypeptide has an apparent molecular weight of approximately 23 kD as assessed by SDS-PAGE under reducing conditions;
wherein the antibody is a monoclonal antibody that inhibits the polypeptide from stimulating phosphorylation of Fly4; and
wherein the molecule specifically binds the polypeptide.
35. The molecule of claim 34 , wherein the polypeptide binds and stimulates phosphorylation of VEGFR-2, and wherein the antibody inhibits the polypeptide from stimulating phosphorylation of VEGFR-2.
36. A molecule that comprises an antigen-binding fragment of an antibody that specifically binds with a soluble polypeptide ligand of Flt4 receptor tyrosine kinase, wherein the soluble polypeptide ligand comprises a polypeptide encoded by the cDNA insert of plasmid pFlt4-L, having ATCC Accession No. 97231; wherein the polypeptide has a molecular weight of about 23 kD as assessed by SDS-PAGE under reducing conditions; and wherein binding of the antibody to the polypeptide ligand blocks activation of Flt-4 receptor tyrosine kinase by the polypeptide ligand; and
wherein the molecule specifically binds the polypeptide.