Methods of treatment using ctla4 molecules

Abstract

The present invention provides soluble CTLA4 mutant molecules which bind with greater avidity to the CD80 and/or CD86 antigen than wild type CTLA4 or non-mutated CTLA4Ig. The soluble CTLA4 molecules have a first amino acid sequence comprising the extracellular domain of CTLA4, where certain amino acid residues within the S25-R33 region and M97-G107 region are mutated. The mutant molecules of the invention may also include a second amino acid sequence which increases the solubility of the mutant molecule.

What is claimed is: 
     
         1 . A method for inhibiting graft versus host disease in a subject which comprises administering to the subject a soluble CTLA4 molecule comprising an extracellular domain as shown in SEQ ID NO:8 beginning with alanine at position 26 or methionine at position 27 and ending with aspartic acid at position 150. 
     
     
         2 . The method of  claim 1  wherein the soluble CTLA4 molecule further comprising an amino acid sequence which alters the solubility, affinity or valency of the soluble CTLA4 mutant molecule. 
     
     
         3 . The method of  claim 2 , wherein the soluble CTLA4 molecule comprises a human immunoglobulin constant region. 
     
     
         4 . The method of  claim 3  wherein the immunoglobulin constant region is mutated to reduce effector function. 
     
     
         5 . The method of  claim 3  wherein the immunoglobulin constant region comprises a hinge, CH2 and CH3 regions of an immunoglobulin molecule. 
     
     
         6 . The method of  claim 5 , wherein any or all of the cysteine residues within the immunoglobulin hinge are substituted with serine. 
     
     
         7 . The method of  claim 6  wherein a cysteine at position 156 is substituted with a serine, a cysteine at position 162 is substituted with a serine, and a cysteine at position 165 is substituted with a serine, as shown in SEQ ID NO:8. 
     
     
         8 . The method of  claim 1 , wherein the soluble CTLA4 molecule further comprising a junction amino acid residue and an immunoglobulin, where the junction amino acid residue is located between the amino acid sequence which ends with aspartic acid at position 150 and the immunoglobulin. 
     
     
         9 . The method of  claim 8 , wherein the junction amino acid residue is glutamine. 
     
     
         10 . A method for inhibiting graft versus host disease in a subject which comprises administering to the subject a soluble CTLA4-Ig molecule comprising the amino acid sequence shown in SEQ ID NO:8 beginning with alanine at position 26 or methionine at position 27 and ending with lysine at position 383.