Timp3 as vegf inhibitor

Abstract

Polypeptides or proteins comprising tissue inhibitor of mettaloproteinases-3 (TIMP3) or variants of TIMP3 can be used to substantially inhibit vascular endothelial growth factor (VEGF) binding to VEGF receptor-2 (VEGFR2/KDR/Flk-1)) without substantially inhibiting VEGF binding to VEGF receptor 1 (VEGFR1/Flt-1).

1 . A purified polypeptide comprising SEQ ID NO: 9; wherein said polypeptide inhibits the binding of VEGF to VEGFR2 (KDR/Flk1) without substantially inhibiting the binding of VEGF to VEGFR1 (Flt1). 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The polypeptide of  claim 1  being free of mettaloproteinase inhibiting activity. 
     
     
         5 . The polypeptide of  claim 1 , being linked to a therapeutic agent. 
     
     
         6 . The polypeptide of  claim 5 , the therapeutic agent being at least one of a chemotherapeutic agent, a radiotherapeutic agent, cytotoxic agent, anti-angiogenic agent, coagulent, or anti-tubulin drug. 
     
     
         7 - 8 . (canceled) 
     
     
         9 . The polypeptide of  claim 1 , being a fusion protein. 
     
     
         10 . The polypeptide of  claim 1  being capable of inhibiting the proliferation of vascular endothelial cells mediated by VEGF. 
     
     
         11 . The polypeptide of  claim 1 , wherein said polypeptide is capable of inhibiting angiogensis mediated by VEGF. 
     
     
         12 . A pharmaceutical composition comprising the polypeptide of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         13 . A therapeutic kit comprising the pharmaceutical composition of  claim 12 . 
     
     
         14 - 21 . (canceled) 
     
     
         22 . A method of targeting or delivering at least one diagnostic agent or therapeutic agent to cells expressing VEGFR2 (KDR/Flk1), the method comprising linking the at least one diagnostic agent or therapeutic agent to a polypeptide comprising at least a portion of the C-terminal domain of TIMP3, the at least portion of the C-terminal domain of TIMP3 comprising SEQ ID NO: 9. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 22 , the therapeutic agent comprising at least one of chemotherapeutic agent, a radiotherapeutic agent, cytotoxic agent, anti-angiogenic agent, coagulent, or anti-tubulin drug. 
     
     
         25 - 29 . (canceled) 
     
     
         30 . A method of treating an angiogenic disease, the method comprising:
 contacting a tissue or a population of angiogenic vessels that contain vascular endothelial cells that express VEGFR2 with a composition comprising a biologically effective amount of at least one of TIMP3 or fragment of TIMP3 comprising SEQ ID NO: 9 under conditions effective to inhibit VEGF induced angiogenesis and to treat angiogenic disease.   
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 30 , the composition not inhibiting VEGF binding to VEGFR1. 
     
     
         33 . The method of  claim 30 , the composition comprising the fragment of TIMP3, the fragment being free of SEQ ID NO: 3. 
     
     
         34 . The method of  claim 30 , the composition comprising the fragment of TIMP3, the fragment being free of metalloproteinase inhibiting activity. 
     
     
         35 . The method of  claim 30 , the VEGF inhibiting TIMP3 fragment being linked to a therapeutic agent. 
     
     
         36 . The method of  claim 35 , the therapeutic agent comprising at least one of a chemotherapeutic agent, a radiotherapeutic agent, cytotoxic agent, anti-angiogenic agent, coagulent, or anti-tubulin drug.