Multivalent compounds for crosslinking receptors and uses thereof

Abstract

Synthetic crosslinking homobivalent and heterobivalent compounds have been designed and developed. These compounds are low in molecular weight, have antagonistic or agonistic activity, and induce the association between two identical or similar natural receptors (homobivalent compounds) or induce the association between two different natural receptors (heterobivalent compounds).

1 - 56 . (canceled)  
     
     
         57 . A compound having the structure  
       
         
           
           
               
               
           
         
       
       wherein B is boron, each of Y 1  and Y 2  is independently selected from the group consisting of a hydroxyl moiety and a reactive moiety that converts to a hydroxyl moiety under physiological conditions, A 3 -A 4  has the structure  
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       is an amino acid having a structure selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       R represents the side chain of the amino acid, L is a linker molecule (i) having a molecular weight ranging between about 100 daltons and about 2000 daltons, and (ii) having a span ranging from about 20 Å to about 300 Å, and P is an antibody or antibody fragment, and wherein the compound binds to at least one DPIV protein.  
     
     
         58 . The compound of  claim 57 , wherein the each Y 1  and Y 2  is OH.  
     
     
         59 . The compound of  claim 57 , wherein the C bonded to the B is in an L-configuration.  
     
     
         60 . The compound of  claim 57 , wherein L is selected from the group consisting of adipic acid, a polypeptide containing from 2 to 15 amino acids, 1,4-diaminobutane, 1,4-dithiobutane and dithiothreitol.  
     
     
         61 . The compound of  claim 57 , wherein L has the structure  
         -[G] m -[J] p -[G] q   (a) wherein [J] is selected from the group consisting of a CH 2  group and a hydrocarbon chain,    (b) wherein [G] is a side chain of an amino acid selected from the group consisting of the side chains of lysine, cysteine, glutamic acid, aspartic acid, histidine, arginine, glutamine, and asparagine, and    (c) wherein m, p, and q are independently selected integers from 1 to 50, inclusive.    
     
     
         62 . The compound of  claim 57 , wherein the antibody or antibody fragment binds to an epitope expressed on a cell surface.  
     
     
         63 . The compound of  claim 62 , wherein the cell surface is a T cell surface or a B cell surface.  
     
     
         64 . The compound of  claim 62 , wherein the epitope is a portion of TCR/CD3, CD4, CD8, CD10, CD26, CD28 or CD45.  
     
     
         65 . A method for stimulating an immune response comprising administering the compound of  claim 57  to a subject in need thereof.