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US 2012/0071406 A1Published application
Modified vegf-a with improved angiogenic properties
AssigneeVegenics Pty Limited
InventorsKARI ALITALO, Tuomas Tammela, Salla Keskitalo, Katri Pajusola, Markku M. Jeltsch, Seppo Yla-Herttuala, Terhi Karpanen, Ulf Eriksson, Marko J. T. Uutela
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Abstract
The present invention is directed to methods and compositions for making and using chimeric polypeptides that comprise a VEGFR-2 ligand. The chimeric molecules of the present invention retain VEGFR-2 binding activity and an enhanced angiogenic activity as compared to native VEGF-A.
Claims27
A construct comprising:
- an RTK binding domain, at least one flanking domain, and at least one linkage that connects the RTK binding domain to the at least one flanking domain;
- wherein the RTK binding domain comprises an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of:
- mammalian VEGF-A RTK binding domain amino acid sequences;
- mammalian VEGF-B RTK binding domain amino acid sequences;
- mammalian VEGF-C RTK binding domain amino acid sequences;
- mammalian VEGF-D RTK binding domain amino acid sequences;
- mammalian VEGF-E RTK binding domain amino acid sequences;
- mammalian P1GF RTK binding domain amino acid sequences;
- mammalian PDGF-A RTK binding domain amino acid sequences;
- mammalian PDGF-B RTK binding domain amino acid sequences;
- mammalian PDGF-C RTK binding domain amino acid sequences;
- and mammalian PDGF-D RTK binding domain amino acid sequences;
- wherein the construct and the RTK binding domain bind to the extracellular domain of at least one receptor tyrosine kinase selected from the group consisting of:
- VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha, and PDGFR-beta;
- and
- wherein the at least one flanking domain comprises an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of:
- a mammalian VEGF-C amino-terminal propeptide;
- a mammalian VEGF-C carboxy-terminal propeptide;
- a mammalian VEGF-D amino-terminal propeptide;
- a mammalian VEGF-D carboxy-terminal propeptide;
- a mammalian TGF-β1 LAP peptide;
- and fragments thereof that are effective to bind extracellular matrix proteins or neuropilin proteins;
- with the proviso that when the RTK binding domain is at least 90% identical to a VEGF-C RTK binding domain amino acid sequence, the at least one flanking domain is not at least 90% identical to a VEGF-C pro-peptide;
- and when the RTK binding domain is at least 90% identical to a VEGF-D RTK binding domain amino acid sequence, the at least one flanking domain is not at least 90% identical to a VEGF-D pro-peptide.
21 more elements
2-18. (canceled)
A construct comprising:
- an RTK binding domain, a CUB domain, and at least one linkage that connects the RTK binding domain to the CUB domain;
- wherein the RTK binding domain comprises an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of:
- mammalian VEGF-A RTK binding domain amino acid sequences;
- mammalian VEGF-B RTK binding domain amino acid sequences;
- mammalian VEGF-C RTK binding domain amino acid sequences;
- mammalian VEGF-D RTK binding domain amino acid sequences;
- mammalian VEGF-E RTK binding domain amino acid sequences;
- mammalian P1GF RTK binding domain amino acid sequences;
- mammalian PDGF-A RTK binding domain amino acid sequences;
- and mammalian PDGF-B RTK binding domain amino acid sequences;
- wherein the CUB domain comprises an amino acid sequence that is at least 90% identical to an amino acid sequence selected from the group consisting of PDGF-C CUB domain amino acid sequences and PDGF-D CUB domain amino acid sequences;
- and
- wherein the construct and the RTK binding domain bind to the extracellular domain of at least one receptor tyrosine kinase selected from the group consisting of:
- VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha, and PDGFR-beta.
11 more elements
31-33. (canceled)
36-44. (canceled)
46-50. (canceled)
52-53. (canceled)
56-59. (canceled)
61-73. (canceled)
Dependencies are inferred from the claim text.