Methods for inhibiting an immune response by blocking the GP39/CD40 and CTLA4/CD28/B7 pathways and compositions for use therewith

Abstract

The present invention provides a method for inhibiting an immune reponse and a method for inhibiting rejection of transplanted tissues. This method comprises preventing an endogenous molecule on a cell selected from the group consisting of gp39 and CD40 antigens from binding its endogenous ligand and preventing an endogenous molecule on a cell selected from the group consisting of CTLA4, CD28, and B7 antigens from binding its endogenous ligand. The prevention of such molecules from binding their ligand thereby blocks two independent signal pathways and inhibits the immune response resulting in transplanted tissue rejection.

1 . A method for inhibiting rejection of a transplanted tissue comprising: 
 a) contacting a B7-positive cell with a first soluble ligand which recognizes and binds the B7 antigen, and    b) contacting a gp39-positive cell with a second soluble ligand which recognizes and binds the gp39 antigen,    the binding of the B7-positive cell to the first soluble ligand thereby blocking the reaction of the B7 antigen with endogenous CTLA4 or CD28 and the binding of the gp39 antigen to the second soluble ligand thereby blocking the reaction of gp39 antigen with endogenous CD40, the blockage thereby inhibiting the immune response.    
     
     
         2 . (canceled)  
     
     
         3 . (canceled)  
     
     
         4 . The method of  claim 1 , wherein the first soluble ligand is a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4.  
     
     
         5 . The method of  claim 4 , wherein the ligand is CTLA4Ig fusion protein.  
     
     
         6 . (canceled)  
     
     
         7 . The method of  claim 5 , wherein the CTLA4Ig fusion protein is CTLA4Ig designated ATCC 68629.  
     
     
         8 . (canceled)  
     
     
         9 . (canceled)  
     
     
         10 . (canceled)  
     
     
         11 . The method of  claim 1 , wherein the second soluble ligand for the gp39 antigen is a monoclonal antibody reactive with the gp39 antigen.  
     
     
         12 . (canceled)  
     
     
         13 . The method of  claim 4 , wherein the extracellular portion of CTLA4 is joined to a non-CTLA4 protein sequence.  
     
     
         14 . The method of  claim 13 , wherein the non-CTLA4 protein sequence is at least a portion of an immunoglobulin molecule.  
     
     
         15 . (canceled)  
     
     
         16 . (canceled)  
     
     
         17 . A method for inhibiting an immune response comprising: 
 a) preventing an endogenous antigen on a cell selected from the group consisting of gp39 and CD40 from binding its endogenous ligand; and    b) preventing an endogenous antigen on a cell selected from the group consisting of CTLA4, CD28, and B7 from binding its endogenous ligand,    the prevention of such antigens from binding their ligand thereby blocking two independent cell signals and inhibiting the immune response.    
     
     
         18 . The method of  claim 17 , wherein: 
 a) the step of preventing the endogenous gp39 antigen from binding its endogenous ligand comprises contacting a gp39-positive cell with a soluble ligand which recognizes and binds the gp39 antigen,    b) the step of preventing the endogenous CTLA4 antigen from binding its endogenous ligand comprises contacting a B7-positive cell with a soluble ligand which recognizes and binds the B7 antigen,    the binding of the gp39-positive cell to its soluble ligand of step (a) thereby blocking the reaction of endogenous gp39 antigen with endogenous CD40, the binding of the B7-positive cell to its soluble ligand of step (b) thereby blocking the reaction of the endogenous B7 antigen with endogenous CTLA4, the blockage thereby inhibiting the immune response.    
     
     
         19 . (canceled)  
     
     
         20 . (canceled)  
     
     
         21 . The method of  claim 17 , wherein: 
 a) the step of preventing the endogenous CD40 antigen from binding its endogenous ligand comprises contacting a CD40-positive cell with a soluble ligand which recognizes and binds the CD40 antigen,    b) the step of preventing the endogenous CTLA4 antigen from binding its endogenous ligand comprises contacting a B7-positive cell with a soluble ligand which recognizes and binds the B7 antigen,    the binding of the CD40-positive cell to its soluble ligand of step (a) thereby blocking the reaction of endogenous CD40 antigen with endogenous gp39, the binding of the B7-positive cell to its soluble ligand of step (b) thereby blocking the reaction of the B7 antigen with endogenous CTLA4, the blockage thereby inhibiting the immune response.    
     
     
         22 . The method of  claim 21 , wherein the soluble ligand of step (a) is a monoclonal antibody directed against CD40.  
     
     
         23 . The method of  claim 21 , wherein the soluble ligand of step (b) is CTLA4Ig.  
     
     
         24 . The method of  claim 17 , wherein: 
 a) the step of preventing the endogenous gp39 antigen from binding its endogenous ligand comprises contacting a gp39-positive cell with a soluble ligand which recognizes and binds the gp39 antigen,    b) the step of preventing the endogenous CD28 antigen from binding its endogenous ligand comprises contacting a B7-positive cell with a soluble ligand which recognizes and binds the B7 antigen,    the binding of the gp39-positive cell to its soluble ligand of step (a) thereby blocking the reaction of gp39 antigen with endogenous CD40, the binding of the B7-positive cell to its soluble ligand of step (b) thereby blocking the reaction of the B7 antigen with endogenous CD28, the blockage thereby inhibiting the immune response.    
     
     
         25 . (canceled)  
     
     
         26 . (canceled)  
     
     
         27 . The method of  claim 17 , wherein: 
 a) the step of preventing the endogenous CD40 antigen from binding its endogenous ligand comprises contacting a CD40-positive cell with a soluble ligand which recognizes and binds the CD40 antigen,    b) the step of preventing the endogenous B7 antigen from binding its endogenous ligand comprises contacting a CD28-positive cell with a soluble ligand which recognizes and binds the CD28 antigen,    the binding of the CD40-positive cell to the soluble ligand of step (a) thereby blocking the reaction of CD40 antigen with endogenous gp39, the binding of the CD28-positive cell to the soluble ligand of step (b) thereby blocking the reaction of the CD28 antigen with endogenous B7, the blockage thereby inhibiting the immune response.    
     
     
         28 . The method of  claim 27 , wherein the soluble ligand of step (a) is a monoclonal antibody directed against CD40.  
     
     
         29 . (canceled)  
     
     
         30 . The method of  claim 17 , wherein: 
 a) the step of preventing the endogenous CD40 antigen from binding its endogenous ligand comprises contacting a CD40-positive cell with a soluble ligand which recognizes and binds the CD40 antigen,    b) the step of preventing the endogenous B7 antigen from binding its endogenous ligand comprises contacting a CTLA4-positive cell with a soluble ligand which recognizes and binds the CTLA4 antigen,    the binding of the CD40-positive cell to the soluble ligand of step (a) thereby blocking the reaction of CD40 antigen with endogenous gp39, the binding of the CTLA4- or CD28-positive cell to the soluble ligand of step (b) thereby blocking the reaction of the CTLA4 antigen with endogenous B7, the blockage thereby inhibiting the immune response.    
     
     
         31 . (canceled)  
     
     
         32 . (canceled)  
     
     
         33 . The method of  claim 17 , wherein: 
 a) the step of preventing the endogenous CD40 antigen from binding its endogenous ligand comprises contacting a gp39-positive cell with a soluble ligand which recognizes and binds the gp39 antigen,    b) the step of preventing the endogenous B7 antigen from binding its endogenous ligand comprises contacting a CD28-positive cell with a soluble ligand which recognizes and binds the CD28 antigen,    the binding of the gp40-positive cell to the soluble ligand of step (a) thereby blocking the reaction of gp39 antigen with endogenous CD40, the binding of the CD28-positive cell to the soluble ligand of step (b) thereby blocking the reaction of the CD28 antigen with endogenous B7, the blockage thereby inhibiting the immune response.    
     
     
         34 . The method of  claim 33 , wherein the soluble ligand of step (a) is a monoclonal antibody reactive with the gp39 antigen.  
     
     
         35 . (canceled)  
     
     
         36 . The method of  claim 17 , wherein: 
 a) the step of preventing the endogenous CD40 antigen from binding its endogenous ligand comprises contacting a gp39-positive cell with a soluble ligand which recognizes and binds the gp39 antigen,    b) the step of preventing the endogenous B7 antigen from binding its endogenous ligand comprises contacting a CTLA4-positive cell with a soluble ligand which recognizes and binds the CTLA4 antigen,    the binding of the CD40-positive cell to the soluble ligand of step (a) thereby blocking the reaction of gp39 antigen with endogenous CD40, the binding of the CTLA4-positive cell to the soluble ligand of step (b) thereby blocking the reaction of the CTLA4 antigen with endogenous B7, the blockage thereby inhibiting the immune response.    
     
     
         37 . The method of  claim 36 , wherein the soluble ligand of step (a) is a monoclonal antibody reactive with the gp39 antigen.  
     
     
         38 .- 50 . (canceled)