Methods for treating neoplastic disease characterized by vascular endothelial growth factor D expression, for screening for neoplastic disease or metastatic risk, and for maintaining vascularization of tissue

Abstract

A method for treating and alleviating disease characterized by the expression of VEGF-D involving screening to find an organism with tumor cells expressing VEGF-D and administering an effective amount of a VEGF-D antagonist; a method for screening for neoplastic diseas, where detection of VEGF-D on or in a sample such as tumor cells, blood vessel endothelial cells or lymph vessel endothelial cells indicates neoplastic disease; a method for promoting and maintaining vascularization of normal tissue in an organism involving administering a vascularization promoting amount of VEGF-D or a fragment or analog thereof to the organism; a method for screening tumors for metastatic risk involving detecting expression of VEFG-D by a tumor which indicates metastatic risk; and a method of detecting micro-metastasis of neoplastic disease involving detection of VEGF-D on or in a tissue sample which indicates metastasis of a neoplastic disease.

What is claimed is:  
     
         1 . A method of treating an organism suffering from a neoplastic disease characterized by the expression of VEGF-D by a tumor, comprising: 
 screening an organism to determine a presence or an absence of VEGF-D-expressing tumor cells;    selecting said organism determined from the screening to have a tumor expressing VEGF-D; and    administering an effective amount of a VEGF-D antagonist in the vicinity of said tumor to prevent binding of VEGF-D to its corresponding receptor.    
     
     
         2 . A method according to  claim 1 , wherein said organism is a mammal.  
     
     
         3 . A method according to  claim 1 , wherein said VEGF-D antagonist is co-administered with a cytotoxic agent.  
     
     
         4 . A method according to  claim 1 , wherein said antagonist is administered in a composition further comprising at least one pharmaceutical carrier or adjuvant.  
     
     
         5 . A method according to  claim 1 , wherein said neoplastic disease is selected from the group consisting of malignant melanoma, breast ductal carcinoma, squamous cell carcinoma, prostate cancer and endometrial cancer.  
     
     
         6 . A method according to  claim 1 , wherein said antagonist is a monoclonal antibody which specifically binds VEGF-D and blocks VEGF-D binding to VEGF Receptor-2 or VEGF Receptor-3.  
     
     
         7 . A method according to  claim 6 , wherein said antibody binds to the VEGF homology domain of VEGF-D.  
     
     
         8 . A method for screening for a neoplastic disease characterized by an increase in expression of VEGF-D, comprising: 
 obtaining a sample from an organism suspected of being in a neoplastic disease state characterized by an increase in expression of VEGF-D;    exposing said sample to a composition comprising a compound that specifically binds VEGF-D;    washing said sample; and    screening for said disease by detecting the presence, quantity or distribution of said compound in said tissue sample, where detection of VEGF-D in cells in or around a potential neoplastic growth is indicative of a neoplastic disease.    
     
     
         9 . A method according to  claim 8 , wherein said compound is a monoclonal antibody which specifically binds VEGF-D.  
     
     
         10 . A method according to  claim 8 , wherein said antibody binds to the VEGF homology domain of VEGF-D.  
     
     
         11 . A method according to  claim 8 , wherein a said compound includes a detectable label.  
     
     
         12 . A method according to  claim 8 , wherein said neoplastic disease is selected from the group consisting of malignant melanoma, breast ductal carcinoma, squamous cell carcinoma, prostate cancer and endometrial cancer.  
     
     
         13 . A method according to  claim 8 , wherein said sample is a human tissue sample.  
     
     
         14 . A method for screening for a neoplastic disease characterized by an increase in expression of VEGF-D, comprising: 
 obtaining a sample from an organism suspected of being in a neoplastic disease state characterized by an increase in expression of VEGF-D;    exposing said sample to a composition comprising a compound that specifically binds VEGF-D;    washing said sample; and    screening for said disease by detecting the presence, quantity or distribution of said compound in said sample, where detection of VEGF-D in or on blood vessel endothelial cells in or around a potential neoplastic growth is indicative of a neoplastic disease.    
     
     
         15 . A method according to  claim 14 , wherein said compound is a monoclonal antibody which specifically binds VEGF-D.  
     
     
         16 . A method according to  claim 15 , wherein said antibody binds to the VEGF homology domain of VEGF-D.  
     
     
         17 . A method according to  claim 14 , wherein a said compound includes a detectable label.  
     
     
         18 . A method for screening for a neoplastic disease characterized by an increase in blood vessel vascular endothelial cells, comprising: 
 obtaining a sample from an organism suspected of being in a neoplastic disease state characterized by an increase in blood vessel vascular endothelial cells;    exposing said sample to a composition comprising a compound that specifically binds VEGF-D;    washing said sample; and    screening for disease by detecting the presence, quantity or distribution of said compound in said sample, where detection of VEGF-D in or on blood vessel endothelial cells in or around a potential neoplastic growth is indicative of a neoplastic disease.    
     
     
         19 . A method according to  claim 18 , wherein said compound is a monoclonal antibody which specifically binds VEGF-D.  
     
     
         20 . A method according to  claim 19 , wherein said antibody binds to the VEGF homology domain of VEGF-D.  
     
     
         21 . A method according to  claim 18 , wherein a said compound includes a detectable label.  
     
     
         22 . A method according to  claim 18 , further comprising exposing the sample to a second compound that specifically binds to at least one of VEGFR-2 and VEGFR-3, and wherein the screening step comprises detection of the compound that binds VEGF-D and the second compound bound to blood vessel vascular endothelial cells, to determine the presence, quantity or distribution of blood vessel endothelial cells having both VEGF-D and at least one of VEGFR-2 and VEGFR-3 in or around a potential neoplastic growth.  
     
     
         23 . A method for screening for a neoplastic disease characterized by an increase in lymph vessel endothelial cells, comprising: 
 obtaining a sample from an organism suspected of being in a neoplastic disease state characterized by an increase in lymph vessel endothelial cells;    exposing said sample to a composition comprising a compound that specifically binds VEGF-D;    washing said sample; and    screening for said disease by detecting the presence, quantity or distribution of said compound in said sample, where detection of VEGF-D in or on lymph vessel endothelial cells in or around a potential neoplastic growth is indicative of a neoplastic disease.    
     
     
         24 . A method according to  claim 23 , wherein said compound is a monoclonal antibody which specifically binds VEGF-D.  
     
     
         25 . A method according to  claim 24 , wherein said antibody binds to the VEGF homology domain of VEGF-D.  
     
     
         26 . A method according to  claim 23 , wherein a said compound includes a detectable label.  
     
     
         27 . A method according to  claim 23 , further comprising exposing the sample to a second compound that specifically binds to VEGFR-3, and wherein the screening step comprises detection of the compound that binds VEGF-D and the second compound bound to lymph vessel endothelial cells, to determine the presence, quantity or distribution of lymph vessel endothelial cells having both VEGF-D and VEGFR-3 in or around a potential neoplastic growth.  
     
     
         28 . A method for maintaining the vascularization of tissue in an organism, comprising administering to said organism in need of such treatment an effective amount of VEGF-D, or a fragment or analog thereof having the biological activity of VEGF-D.  
     
     
         29 . A method of treating an organism suffering from a neoplastic disease characterized by the expression of VEGF-D by a tumor, comprising administering an effective amount of a VEGF-D antagonist in the vicinity of said tumor to prevent binding of VEGF-D to its corresponding receptor.  
     
     
         30 . A method according to  claim 29 , wherein said organism is a mammal.  
     
     
         31 . A method according to  claim 29 , wherein said VEGF-D antagonist is co-administered with a cytotoxic agent.  
     
     
         32 . A method according to  claim 29 , wherein said antagonist is administered in a composition further comprising at least one pharmaceutical carrier or adjuvant.  
     
     
         33 . A method according to  claim 29 , wherein said neoplastic disease is selected from the group consisting of malignant melanoma, breast ductal carcinoma, squamous cell carcinoma, prostate cancer and endometrial cancer.  
     
     
         34 . A method according to  claim 29 , wherein said antagonist is a monoclonal antibody which specifically binds VEGF-D and blocks VEGF-D binding to VEGF Receptor-2 or VEGF Receptor-3.  
     
     
         35 . A method according to  claim 34 , wherein said antibody binds to the VEGF homology domain of VEGF-D.  
     
     
         36 . A method of screening a tumor for metastatic risk, said method comprising: 
 exposing a tumor sample to a composition comprising a compound that specifically binds VEGF-D;    washing said sample; and    screening for metastatic risk by detecting the presence, quantity or distribution of said compound in said sample, where expression of VEGF-D by said tumor is indicative of metastatic risk.    
     
     
         37 . A method according to  claim 36 , wherein said compound is a monoclonal antibody which specifically binds VEGF-D.  
     
     
         38 . A method according to  claim 37 , wherein said antibody binds to the VEGF homology domain of VEGF-D.  
     
     
         39 . A method according to  claim 36 , wherein a said compound includes a detectable label.  
     
     
         40 . A method of detecting micro-metastasis of a neoplastic disease state characterized by an increase in expression of VEGF-D comprising: 
 obtaining a tissue sample from a site spaced from a neoplastic growth in an organism in said neoplastic disease state;    exposing said sample to a composition comprising a compound that specifically binds VEGF-D;    washing said sample; and    screening for said metastasis of said neoplastic disease by detecting the presence, quantity or distribution of said compound in said tissue sample, where detection of VEGF-D in said tissue sample is indicative of metastasis of said neoplastic disease.    
     
     
         41 . A method according to  claim 40 , wherein said tissue sample is a lymph node from tissue surrounding said neoplastic growth.  
     
     
         42 . A method according to  claim 40 , wherein said compound is a monoclonal antibody which specifically binds VEGF-D.  
     
     
         43 . A method according to  claim 42 , wherein said antibody binds to the VEGF homology domain of VEGF-D.  
     
     
         44 . A method according to  claim 40 , wherein a said compound includes a detectable label.