Conjugates comprising galactose alpha 1,3 galactosyl epitopes and methods of using same

Abstract

This invention provides conjugates useful for xenotransplantation which comprise a galactose α1,3 galactosyl (αGal) epitope conjugated to a valency platform molecule, preferably a chemically defined valency platform molecule which allows precise valency. The invention also provides compositions comprising these conjugates, and methods (such as methods for inducing tolerance) using these conjugates and compositions.

We claim:  
     
         1 . A conjugate comprising a valency platform molecule and an αGal epitope, wherein the valency platform molecule has a valency from two to 128.  
     
     
         2 . The conjugate of  claim 1 , wherein the valency platform molecule has a valency of two.  
     
     
         3 . The conjugate of  claim 1 , wherein the valency platform molecule has a valency of four.  
     
     
         4 . The conjugate of  claim 1 , wherein the valency platform molecule has a valency of eight.  
     
     
         5 . The conjugate of  claim 1 , wherein the valency platform molecule has a valency of 16.  
     
     
         6 . The conjugate of  claim 3 , wherein the valency platform molecule is compound 26.  
     
     
         7 . The conjugate of  claim 4 , wherein the valency platform molecule is compound 31.  
     
     
         8 . A conjugate according to  claim 3 , wherein the conjugate has the structure of compound 38.  
     
     
         9 . A conjugate according to  claim 4 , wherein the conjugate has the structure of compound 46.  
     
     
         10 . A conjugate according to  claim 1 , wherein the αGal epitope is 2-[2-(2-acetylthioethoxy)ethoxy]ethyl 3-O-(α-D-galactopyranosyl)-β-D-galactopyranoside.  
     
     
         11 . A conjugate comprising a valency platform molecule and an αGal epitope, wherein the valency platform molecule has a valency of at least two.  
     
     
         12 . A composition comprising the conjugate of  claim 1 .  
     
     
         13 . A composition comprising the conjugate of  claim 3 .  
     
     
         14 . A composition comprising the conjugate of  claim 4 .  
     
     
         15 . A composition comprising the conjugate of  claim 9 .  
     
     
         16 . A method of reducing circulating levels of anti-αGal antibody in an individual, comprising administering an effective amount of the conjugate of  claim 1  to the individual.  
     
     
         17 . A method of reducing circulating levels of anti-αGal antibody in an individual, comprising administering an effective amount of the conjugate of  claim 3  to the individual.  
     
     
         18 . A method of reducing circulating levels of anti-αGal antibody in an individual, comprising administering an effective amount of the conjugate of  claim 7  to the individual.  
     
     
         19 . A method of reducing circulating levels of anti-αGal antibody in an individual, comprising administering the composition of  claim 9  to the individual in an amount sufficient to reduce circulating levels of anti-αGal antibody in the individual.  
     
     
         20 . A method of neutralizing circulating anti-αGal antibody in an individual, comprising administering the composition of  claim 1  to the individual.  
     
     
         21 . A method of inducing tolerance to αGal in an individual, comprising administering an effective amount of the conjugate of  claim 1  to the individual.  
     
     
         22 . A method of inducing tolerance to αGal in an individual, comprising administering an effective amount of the conjugate of  claim 9  to the individual.  
     
     
         23 . A method of detecting an antibody which specifically binds to the conjugate of  claim 1  in a biological sample, comprising (a) contacting antibody in the sample with the conjugate of  claim 1  under conditions that permit the formation of a stable antigen-antibody complex; and (b) detecting stable complex, if any, formed in step (a).  
     
     
         24 . The method of  claim 23 , wherein the antibody is expressed on the surface of a B cell.  
     
     
         25 . A method of performing a xenotransplantation in an individual, comprising the steps of: 
 (a) introducing xenotissue to an individual, wherein the xenotissue comprises an αGal epitope; and    (b) administering the conjugate of  claim 1  to the individual.    
     
     
         26 . The method of  claim 25 , wherein step (b) is performed at least about 30 days before step (a).  
     
     
         27 . A method of performing a xenotransplantation in an individual, comprising the steps of: 
 (a) introducing xenotissue to an individual, wherein the xenotissue comprises an αGal epitope; and    (b) administering the conjugate of  claim 9  to the individual.    
     
     
         28 . The method of  claim 27 , wherein step (b) is performed at least about 30 days before step (a).  
     
     
         29 . A method of suppressing rejection of a transplanted tissue comprising an αGal epitope in an individual, said method comprising administering the conjugate of  claim 1  to the individual in an amount sufficient to suppress rejection.  
     
     
         30 . A method of suppressing rejection of a transplanted tissue comprising an α Gal epitope in an individual, said method comprising administering the conjugate of  claim 9  to the individual in an amount sufficient to suppress rejection.