US2015005235A1PendingUtilityA1

Polypeptides Targeting Vascular Endothelial Growth Factor Receptor-2 and Alpha V Beta 3 Integrin

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Assignee: UNIV LELAND STANFORD JUNIORPriority: Jan 18, 2009Filed: Sep 3, 2014Published: Jan 1, 2015
Est. expiryJan 18, 2029(~2.5 yrs left)· nominal 20-yr term from priority
Inventors:Jennifer R. CochranAdam P. SilvermanDouglas JonesNiv Papo
A61P 35/00A61P 27/02A61P 17/06A61P 19/02C07K 14/515A61K 38/1866A61K 2123/00A61K 38/18C07K 14/475A61K 47/51A61K 38/1858
62
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Claims

Abstract

Polypeptides comprising variant vascular endothelial growth factor sequences are provided. The polypeptides are useful in cancer imaging, cancer diagnosis, monitoring and treatment as well as treatment of diseases characterized by excessive neovascularization.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A vascular endothelial growth factor (VEGF) variant polypeptide, comprising:
 (a) a first polypeptide encoding VEGF, and   (b) a second polypeptide encoding an integrin-recognition RGD motif containing loop;   wherein the VEGF variant polypeptide is a single-chain.   
     
     
         2 . The VEGF variant polypeptide of  claim 1 , wherein the VEGF variant polypeptide exhibits high affinity to alpha v beta 3 integrin. 
     
     
         3 . The VEGF variant polypeptide of  claim 1 , wherein the VEGF variant polypeptide exhibits high affinity to VEGF receptor-2 (VEGFR2). 
     
     
         4 . The VEGF variant polypeptide of  claim 1 , wherein the VEGF variant polypeptide is a VEGF antagonist. 
     
     
         5 . The VEGF variant polypeptide of  claim 1 , wherein the VEGF variant polypeptide is an alpha v beta 3 integrin antagonist. 
     
     
         6 . The VEGF variant polypeptide of  claim 1 , wherein the second polypeptide is a VEGF polypeptide. 
     
     
         7 . The VEGF variant polypeptide of  claim 6 , wherein the integrin-recognition RGD motif containing loop replaces loop 1, loop 2, or loop 3, of the second VEGF polypeptide. 
     
     
         8 . The VEGF variant polypeptide of  claim 1 , wherein the integrin-recognition RGD motif containing loop replaces loop 1, loop 2, or loop 3, of the first VEGF polypeptide. 
     
     
         9 . The VEGF variant polypeptide of  claim 1 , wherein the integrin-recognition RGD motif containing loop comprises a sequence selected from the sequences XXRGDX 4 X 5 X 6 X 7 , X 1 X 2 X 3 RGDX 4 X 5 X 6 , and X 1 X 2 X 3 XRGDX 4 X 5 , wherein each X independently corresponds to an amino acid. 
     
     
         10 . The VEGF variant polypeptide of  claim 9 , wherein X 1  of the integrin-recognition RGD motif containing loop is selected from the group consisting of alanine (A), glycine (G), histidine (H), leucine (L), serine (S), threonine (T), isoleucine (I), arginine (R), valine (V), and proline (P). 
     
     
         11 . The VEGF variant polypeptide of  claim 10 , wherein X 1  of the integrin-recognition RGD motif containing loop is proline (P). 
     
     
         12 . The VEGF variant polypeptide of  claim 11 , wherein X 2  of the integrin-recognition RGD motif containing loop is selected from the group consisting of proline (P), leucine (L), asparagine (N), valine (V), isoleucine (I), glycine (G), alanine (A), serine (S), histidine (H), glutamine (Q), arginine (R), tryptophan (W), phenylalanine (F), and threonine (T). 
     
     
         13 . The VEGF variant polypeptide of  claim 12 , wherein X 2  of the integrin-recognition RGD motif containing loop is selected from the group consisting of glycine (G), alanine (A), threonine (T), valine (V), and serine (S). 
     
     
         14 . The VEGF variant polypeptide of  claim 13 , wherein X 3  of the integrin-recognition RGD motif containing loop is selected from the group consisting of glycine (G), alanine (A), threonine (T), valine (V), and serine (S). 
     
     
         15 . The VEGF variant polypeptide of  claim 9 , wherein X 4  of the integrin-recognition RGD motif containing loop is selected from the group consisting of leucine (L), asparagine (N), valine (V), glycine (G), alanine (A), serine (S), histidine (H), glutamic acid (E), aspartic acid (D), cysteine (C), arginine (R), and threonine (T). 
     
     
         16 . The VEGF variant polypeptide of  claim 15 , wherein X 4  of the integrin-recognition RGD motif containing loop is selected from the group consisting of glycine (G), alanine (A), and serine (S). 
     
     
         17 . The VEGF variant polypeptide of  claim 9 , wherein X 5  of the integrin-recognition RGD motif containing loop is selected from the group consisting of glycine (G), alanine (A), proline (P), serine (S), glutamine (Q), asparagine (N), and threonine (T). 
     
     
         18 . The VEGF variant polypeptide of  claim 17 , wherein X 5  of the integrin-recognition RGD motif containing loop selected from the group consisting of glycine (G), serine (S), and proline (P). 
     
     
         19 . The VEGF variant polypeptide of  claim 9 , wherein X 6  of the integrin-recognition RGD motif containing loop is selected from the group consisting of leucine (L), valine (V), glycine (G), alanine (A), serine (S), histidine (H), glutamic acid (E), aspartic acid (D), arginine (R), tyrosine (Y), tryptophan (W), proline (P), and threonine (T). 
     
     
         20 . The VEGF variant polypeptide of  claim 19 , wherein X 6  of the integrin-recognition RGD motif containing loop selected from the group consisting of alanine (A) and valine (V). 
     
     
         21 . The VEGF variant polypeptide of  claim 9 , wherein X 7  of the integrin-recognition RGD motif containing loop is serine (S). 
     
     
         22 . The VEGF variant polypeptide of  claim 1 , wherein the VEGF variant polypeptide further comprises a linker linking the VEGF polypeptide and the polypeptide encoding the integrin-recognition RGD motif containing loop, wherein the linker does not link VEGF polypeptide and the polypeptide encoding the integrin-recognition RGD motif containing loop through a disulfide bond. 
     
     
         23 . The VEGF variant polypeptide of  claim 1 , wherein the first polypeptide is covalently bound to the second polypeptide. 
     
     
         24 . The VEGF variant polypeptide of  claim 1 , wherein the first polypeptide is encoded by SEQ ID NO: 1, SEQ ID: 2, or portions thereof. 
     
     
         25 . The VEGF variant polypeptide of  claim 6 , wherein the first polypeptide is encoded by SEQ ID NO: 1, SEQ ID: 2, or portions thereof. 
     
     
         26 . The VEGF variant polypeptide of  claim 1 , wherein the integrin-recognition RGD motif containing loop is selected from the group consisting of a polypeptide sequence with at least 90% sequence identity to SEQ ID NOs: 9-27. 
     
     
         27 . A pharmaceutical composition comprising a VEGF variant polypeptide according to  claim 1 . 
     
     
         28 . An isolated nucleic acid encoding a VEGF variant polypeptide according to  claim 1 . 
     
     
         29 . A method of inhibiting VEGF-mediated proliferation or migration of endothelial cells, the method comprising contacting an endothelial cell with a VEGF variant polypeptide according to  claim 1 . 
     
     
         30 . A method of inhibiting angiogenesis, the method comprising contacting endothelial cells associated with the angiogenesis with a VEGF variant polypeptide according to  claim 1 .

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