Methods and compositions for the inhibition of cancer metastasis mediated by endothelial adhesion molecules

Abstract

Methods and compositions are disclosed for the inhibition of cancer metastases mediated by endothelial adhesion molecules. The present invention discloses that sialyl Le a and di-sialyl Le a , which are expressed at the surface of cancer cells, function as a binding partner for LEC-CAMs, such as ELAM-1, which are expressed at the surface of endothelial cells. The present invention also discloses that LEC-CAMs, such as ELAM-1, involved in cancer metastasis share a carbohydrate domain common to both sialyl Le a and sialyl Le x . Antibodies, saccharides, glycoconjugates, enzyme inhibitors and other compounds may be used in the methods of the present invention to inhibit the binding of malignant cells to endothelial cells for a variety of purposes in vivo and in vitro.

1 . A method for inhibiting within a biological preparation the binding of malignant cells expressing sialyl Le a  or di-sialyl Le a , to endothelial cells expressing a LEC-CAM, comprising: 
 incubating the biological preparation with at least one agent that inhibits the binding of malignant cells expressing sialyl Le a  or di-sialyl Le a , to endothelial cells expressing a LEC-CAM.    
     
     
         2 . The method of  claim 1  wherein the agent is a saccharide, a glycoconjugate or an antibody that inhibits the binding of sialyl Le a  or di-sialyl Le a  to a LEC-CAM.  
     
     
         3 . A method for inhibiting within a biological preparation the binding of malignant cells expressing sialyl Le a  or di-sialyl Le a , to endothelial cells expressing ELAM-1, comprising: 
 incubating the biological preparation with at least one agent that inhibits the binding of malignant cells expressing sialyl Le a  or di-sialyl Le a , to endothelial cells expressing ELAM-1.    
     
     
         4 . The method of  claim 3  wherein the agent is a saccharide, a glycoconjugate or an antibody that inhibits the binding of sialyl Le a  or di-sialyl Le a  to ELAM-1.  
     
     
         5 . A method for inhibiting within a biological preparation the binding of malignant cells expressing sialyl Le a  or di-sialyl Le a , to endothelial cells expressing a LEC-CAM, comprising: 
 incubating said malignant cells with at least one enzyme inhibitor that inhibits the biosynthesis of sialyl Le a  or di-sialyl Le a  by said malignant cells.    
     
     
         6 . A method for inhibiting within a biological preparation the binding of malignant cells expressing sialyl Le a  or di-sialyl Le a , to endothelial cells expressing ELAM-1, comprising: 
 incubating said malignant cells with at least one enzyme inhibitor that inhibits the biosynthesis of sialyl Le a  or di-sialyl Le a  by said malignant cells.    
     
     
         7 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein x, y and z are independently selected from saccharides or y or z or both are not present, and R is H, OH, lipid, ceramide, or one or more amino acids, with the proviso that x, y and z are not present in the combination wherein x is GlcNAc, y is Gal and z is Glc.  
     
     
         8 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein x, y and z are independently selected from saccharides or y or z or both are not present, and R is H, OH, lipid, ceramide, or one or more amino acids, with the proviso that x, y and z are not present in the combination wherein x is GlcNAc, y is Gal and z is Glc.  
     
     
         9 . A method for inhibiting in a warm-blooded animal the spread of malignant cells expressing sialyl Le a  or di-sialyl Le a , to secondary sites, comprising: 
 administering to a warm-blooded animal an effective amount of at least one agent that inhibits the binding of malignant cells expressing sialyl Le a  or di-sialyl Le a , to endothelial cells expressing a LEC-CAM.    
     
     
         10 . The method of  claim 9  wherein the agent is a saccharide, a glycoconjugate or an antibody that inhibits the binding of sialyl Le a  or di-sialyl Le a  to a LEC-CAM.  
     
     
         11 . A method for inhibiting in a warm-blooded animal the spread of malignant cells expressing sialyl Le a  or di-sialyl Le a , to secondary sites by hematogenous metastases, comprising: 
 administering to a warm-blooded animal an effective amount of at least one agent that inhibits the binding of malignant cells expressing sialyl Le a  or di-sialyl Le a , to endothelial cells expressing ELAM-1.    
     
     
         12 . The method of  claim 11  wherein the agent is a saccharide, a glycoconjugate or an antibody that inhibits the binding of sialyl Le a  or di-sialyl Le a  to ELAM-1.  
     
     
         13 . A method for inhibiting in a warm-blooded animal the spread of malignant cells expressing sialyl Le a  or di-sialyl Le a , to secondary sites, comprising: 
 administering to a warm-blooded animal an effective amount of at least one enzyme inhibitor that inhibits the biosynthesis of sialyl Le a  or di-sialyl Le a  by said malignant cells.    
     
     
         14 . A method for inhibiting in a warm-blooded animal the spread of malignant cells expressing sialyl Le a  or di-sialyl Le a , to secondary sites by hematogenous metastases, comprising: 
 administering to a warm-blooded animal an effective amount of at least one enzyme inhibitor that inhibits the biosynthesis of sialyl Le a  or di-sialyl Le a  by said malignant cells.    
     
     
         15 . A method for inhibiting within a biological preparation the binding of malignant cells expressing sialyl Le a , di-sialyl Le a  or sialyl Le x , to endothelial cells expressing a LEC-CAM, comprising: 
 incubating the biological preparation with at least one agent capable of reacting with both sialyl Le a  and sialyl Le x .    
     
     
         16 . A method for inhibiting within a biological preparation the binding of malignant cells expressing sialyl Le a , di-sialyl Le a  or sialyl Le x , to endothelial cells expressing ELAM-1, comprising: 
 incubating the biological preparation with at least one agent capable of reacting with both sialyl Le a  and sialyl Le x .    
     
     
         17 . A method for inhibiting in a warm-blooded animal the spread of malignant cells expressing sialyl Le a , di-sialyl Le a  or sialyl Le x , to secondary sites, comprising: 
 administering to a warm-blooded animal an effective amount of at least one agent capable of reacting with both sialyl Le a  and sialyl Le x .    
     
     
         18 . A method for inhibiting in a warm-blooded animal the spread of malignant cells expressing sialyl Le a , di-sialyl Le a  or sialyl Le x , to secondary sites by hematogenous metastases, comprising: 
 administering to a warm-blooded animal an effective amount of at least one agent capable of reacting with both sialyl Le a  and sialyl Le x .