CTLA4-Cy4 fusion proteins

Abstract

CTLA4-immunoglobulin fusion proteins having modified immunoglobulin constant region-mediated effector functions, and nucleic acids encoding the fusion proteins, are described. The CTLA4-immunoglobulin fusion proteins comprise two components: a first peptide having a CTLA4 activity and a second peptide comprising an immunoglobulin constant region which is modified to reduce at least one constant region-mediated biological effector function relative to a CTLA4-IgG1 fusion protein. The nucleic acids of the invention can be integrated into various expression vectors, which in turn can direct the synthesis of the corresponding proteins in a variety of hosts, particularly eukaryotic cells. The CTLA4-immunoglobulin fusion proteins described herein can be administered to a subject to inhibit an interaction between a CTLA4 ligand (e.g., B7-1 and/or B7-2) on an antigen presenting cell and a receptor for the CTLA4 ligand (e.g., CD28 and/or CTLA4) on the surface of T cells to thereby suppress an immune response in the subject, for example to inhibit transplantation rejection, graft versus host disease or autoimmune responses.

1 - 55 . (canceled)  
     
     
         56 . A CTLA4-immunoglobulin fusion protein comprising a first peptide having a CTLA4 activity and a second peptide comprising an immunoglobulin constant region which is modified to reduce at least one constant region-mediated biological effector function relative to a CTLA4-IgG1 fusion protein.  
     
     
         57 . A CTLA4-immunoglobulin fusion protein of  claim 56 , wherein the first peptide comprises an extracellular domain of the CTLA4 protein.  
     
     
         58 . A CTLA4-immunoglobulin fusion protein of  claim 57 , wherein the first peptide comprises amino acid residues 1-125 of the human CTLA4 protein.  
     
     
         59 . A CTLA4-immunoglobulin fusion protein of  claim 56 , wherein the immunoglobulin constant region comprises a hinge region, a CH2 domain and a CH3 domain.  
     
     
         60 . A CTLA4-immunoglobulin fusion protein of  claim 59 , wherein the hinge region, the CH2 domain and the CH3 domain are selected from the group consisting of Cγ1, Cγ2, Cγ3 and Cγ4.  
     
     
         61 . A CTLA4-immunoglobulin fusion protein, comprising a first peptide having a CTLA4 activity and a second peptide comprising an immunoglobulin constant region wherein the immunoglobulin constant region comprises a heavy chain CH1 domain, a hinge region, a CH2 domain and a CH3 domain.  
     
     
         62 . The peptide of  claim 61 , wherein the immunoglobulin constant region is modified to reduce at least one constant region-mediated biological effector function.  
     
     
         63 . The peptide of  claim 61 , wherein the first peptide having a CTLA4 activity and the hinge region of the second peptide include at least one cysteine residue available for disulfide bond formation.  
     
     
         64 . The peptide of  claim 62 , wherein the first peptide having a CTLA4 activity and the hinge region of the second peptide include at least one cysteine residue available for disulfide bond formation.  
     
     
         65 . A CTLA4-immunoglobulin fusion protein of  claim 59 , wherein the CH2 domain is modified to reduce biological effector functions.  
     
     
         66 . A CTLA4-immunoglobulin fusion protein of  claim 65 , wherein the biological effector function is selected from the group consisting of complement activation, Fc receptor interaction, and complement activation and Fc receptor interaction.  
     
     
         67 . A CTLA4-immunoglobulin fusion protein of  claim 66 , wherein the CH2 domain is modified by substitution of an amino acid residue located at a position of an intact immunoglobulin heavy chain selected from the group consisting of position 234, position 235 and position 237.  
     
     
         68 . A CTLA4-immunoglobulin fusion protein of  claim 67  comprising an amino acid sequence shown in SEQ ID NO: 24.  
     
     
         69 . A CTLA4-immunoglobulin fusion protein of  claim 68  comprising an amino acid sequence shown in SEQ ID NO: 28.  
     
     
         70 . A CTLA4-immunoglobulin light chain fusion protein, wherein the first peptide comprises a CTLA4 extracellular domain and the second peptide comprises an immunoglobulin kappa light chain constant domain.  
     
     
         71 . An isolated peptide consisting of a CTLA4 extracellular domain produced by a bacterial host cell, wherein said host cell is transfected with an expression vector comprising a nucleotide sequence encoding a CTLA4 extracellular domain.  
     
     
         72 . An isolated peptide consisting of a signal sequence and a CTLA4 extracellular domain produced by a bacterial host cell, wherein said host cell is transfected with an expression vector consisting of a nucleotide sequence encoding a signal sequence and a nucleotide sequence encoding a CTLA4 extracellular domain.  
     
     
         73 . A composition suitable for pharmaceutical administration comprising a CTLA4-immunoglobulin fusion protein of  claim 56 , and a pharmaceutically acceptable carrier.  
     
     
         74 . A composition suitable for pharmaceutical administration comprising a CTLA4-immunoglobulin fusion protein of  claim 58 , and a pharmaceutically acceptable carrier.  
     
     
         75 - 91 . (canceled)