Vascular endothelial growth factor D (VEGF-D) antibodies and vectors, and methods of use

Abstract

VEGF-D, a new member of the PDGF family of growth factors, which among other things stimulates endothelial cell proliferation and angiogenesis and increases vascular permeability, as well as nucleotide sequences encoding it, methods for producing it, antibodies and other antagonists to it, transfected or transformed host cells for expressing it, pharmaceutical compositions containing it, and uses thereof in medical and diagnostic applications.

1 - 28 . (canceled) 
     
     
         29 . An antibody specifically reactive with a polypeptide that comprises an amino acid sequence selected from the sequences of SEQ ID NOS: 3, 5, 8, and 9. 
     
     
         30 - 35 . (canceled) 
     
     
         36 . A vector comprising an anti-sense nucleotide sequence, said anti-sense nucleotide sequence being complementary to at least a part of a VEGF-D genomic DNA sequence or a VEGF-D RNA sequence or a cDNA sequence which encodes VEGF-D or a fragment or analogue thereof which promotes at least one bioactivity selected from vascular permeability, proliferation of endothelial cells and endothelial cell differentiation, whereby said vector can be used to inhibit said at least one bioactivity. 
     
     
         37 - 45 . (canceled) 
     
     
         46 . A method of inhibiting a bioactivity selected from angiogenesis and neovascularization in a mammal, said method comprising the step of administering to said mammal an effective angiogenesis or neovascularization inhibiting amount of a VEGF-D antagonist according to  claim 70 . 
     
     
         47 . A method according to  claim 46 , wherein said VEGF-D antagonist comprises an antibody specific to VEGF-D. 
     
     
         48 . A method according to  claim 46 , wherein said VEGF-D antagonist comprises a polypeptide which binds to endothelial cells but which is unable to stimulate at least one biological activity selected from proliferation of endothelial cells, endothelial cell differentiation and vascular permeability. 
     
     
         49 . A method according to  claim 48 , wherein said endothelial cells are selected from the group consisting of vascular endothelial cells and lymphatic endothelial cells. 
     
     
         50 . A method of inhibiting VEGF-D expression in a mammal comprising the step of transforming target cells expressing VEGF-D with a vector according to  claim 36 . 
     
     
         51 - 52 . (canceled) 
     
     
         53 . A pharmaceutical composition comprising an antibody according to  claim 29 , and a pharmaceutically acceptable carrier or adjuvant. 
     
     
         54 . A pharmaceutical composition according to  claim 53 , wherein said antibody is a monoclonal antibody. 
     
     
         55 - 59 . (canceled) 
     
     
         60 . A method of modulating vascular permeability in a mammal, said method comprising administering to said mammal an effective vascular permeability modulating amount of an antibody according to  claim 29 . 
     
     
         61 - 69 . (canceled) 
     
     
         70 . A VEGF-D antagonist having the capability to inhibit at least one biological activity induced by VEGF-D selected from vascular permeability, endothelial cell proliferation and endothelial cell differentiation, said antagonist binding to VEGF-D or to a VEGF-D receptor, but being less able than VEGF-D to stimulate said at least one biological activity. 
     
     
         71 . A VEGF-D antagonist according to  claim 70 , wherein said antagonist comprises an antibody which selectively binds VEGF-D. 
     
     
         72 . A VEGF-D antagonist according to  claim 71 , wherein said antibody is a monoclonal antibody. 
     
     
         73 . A VEGF-D antagonist according to  claim 71 , wherein said antagonist comprises a VEGF-D polypeptide fragment or analogue which binds to a VEGF-D receptor, but is less able to stimulate said at least one biological activity. 
     
     
         74 . (canceled) 
     
     
         75 . A method of treating fluid accumulation in the heart and/or lung due to increases in vascular permeability in a mammal, said method comprising administering to said mammal an effective vascular permeability decreasing amount of an antagonist according to  claim 70 . 
     
     
         76 . (canceled) 
     
     
         77 . An isolated antisense nucleic acid that comprises a nucleotide sequence that is complementary to at least a part of a VEGF-D genomic DNA sequence or a VEGF-D RNA sequence or a VEGF-D cDNA sequence. 
     
     
         78 . A method of inhibiting VEGF-D expression in a mammalian cell comprising transforming a mammalian cell with an antisense nucleic acid. 
     
     
         79 . The method of  claim 78 , wherein the cell is in vivo and the method comprises administering a composition that comprises the antisense nucleic acid to a mammal.