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US 8,025,886 B2Granted
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.
Claims48
A construct comprising:
- a receptor tyrosine kinase (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 identical to a mammalian VEGF-A RTK binding domain amino acid sequence;
- 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:
- human VEGFR-1 and human VEGFR-2;
- and
- wherein the at least one flanking domain comprises an amino acid sequence that is 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, and fragments of the mammalian VEGF-C carboxy-terminal mammalian propeptide that retain one or more BR3P homology domains of the full-length mammalian VEGF-C carboxy-terminal propeptide.
5 more elements
A construct comprising:
- a receptor tyrosine kinase (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 identical to a mammalian VEGF-A RTK binding domain amino acid sequence;
- 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:
- human VEGFR-1 and human VEGFR-2 and
- wherein the at least one flanking domain comprises an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of the VEGF-C amino-terminal propeptide amino acid sequence of SEQ ID NO:
- 46 and the VEGF-C carboxy-terminal propeptide amino acid sequence of SEQ ID NO:
- 47, wherein the flanking domain is capable of binding to neuropilins or extracellular matrix proteins.
4 more elements
A polynucleotide that comprises a nucleotide sequence that encodes a construct, said construct comprising:
- a receptor tyrosine kinase (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 at least one linkage comprises a peptide bond, whereby the construct comprises a chimeric polypeptide;
- wherein the RTK binding domain comprises an amino acid sequence that is identical to a mammalian VEGF-A RTK binding domain amino acid sequence;
- 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:
- human VEGFR-1 and human VEGFR-2 and
- wherein the at least one flanking domain comprises an amino acid sequence that is 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, and fragments of the mammalian VEGF-C carboxy-terminal propeptide that retain one or more BR3P homology domains of the mammalian VEGF-C carboxy-terminal propeptide.
3 more elements
A polynucleotide that comprises a nucleotide sequence that encodes a construct, said construct comprising:
- a receptor tyrosine kinase (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 at least one linkage comprises a peptide bond, whereby the construct comprises a chimeric polypeptide;
- wherein the RTK binding domain comprises an amino acid sequence that is identical to a mammalian VEGF-A RTK binding domain amino acid sequence;
- 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:
- human VEGFR-1 and human VEGFR-2 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 the VEGF-C amino-terminal propeptide amino acid sequence of SEQ ID NO:
- 46 and the VEGF-C carboxy-terminal propeptide amino acid sequence of SEQ ID NO:
- 47, wherein the flanking domain is capable of binding to neuropilins or extracellular matrix proteins.
4 more elements
Dependencies are inferred from the claim text.