Methods of treatment using CTLA4 mutant molecules
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.
1. A method for treating graft versus host disease in a subject comprising administering to the subject a CTLA4 mutant molecule, wherein the CTLA4 mutant molecule binds CD80 and/or CD86 and comprises an extracellular domain of CTLA4 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, wherein in the extracellular domain, an alanine at position 55 is substituted with a tyrosine, and a leucine at position 130 is substituted with a glutamic acid.
2. A method for treating graft versus host disease in a subject comprising administering to the subject a CTLA4 mutant molecule, wherein the CTLA4 mutant molecule comprises:
(a) an amino acid sequence beginning with methionine at position 27 and ending with aspartic acid at position 150 of SEQ ID NO:4, or
(b) an amino acid sequence beginning with alanine at position 26 and ending with aspartic acid at position 150 of SEQ ID NO:4.
3. A method for treating graft versus host disease in a subject comprising administering to the subject a CTLA4 mutant molecule, wherein the CTLA4 mutant molecule comprises:
(a) an amino acid sequence beginning with methionine at position 27 and ending with aspartic acid at position 150 of SEQ ID NO:4 or a portion thereof that binds CD80 and/or CD86, or
(b) an amino acid sequence beginning with alanine at position 26 and ending with aspartic acid at position 150 of SEQ ID NO:4 or a portion thereof that binds CD80 and/or CD86.
4. The method of claim 2 further comprising an amino acid sequence which alters the solubility or affinity of the CTLA4 mutant molecule.
5. The method of claim 4 , wherein the amino acid sequence which alters the solubility or affinity comprises an immunoglobulin.
6. The method of claim 5 , wherein the immunoglobulin is an immunoglobulin constant region or portion thereof.
7. The method of claim 6 , wherein the immunoglobulin constant region or portion thereof is mutated to reduce effector function.
8. The method of claim 6 , wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule.
9. The method of claim 7 , wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule.
10. A method for treating graft versus host disease in a subject comprising administering to the subject a CTLA4 mutant molecule, wherein the CTLA4 mutant molecule comprises:
(a) an amino acid sequence beginning with methionine at position 27 and ending with lysine at position 383 of SEQ ID NO:4, or
(b) an amino acid sequence beginning with alanine at position 26 and ending with lysine at position 383 of SEQ ID NO:4.
11. A method for treating graft versus host disease in a subject comprising administering to the subject a CTLA4 mutant molecule encoded by the nucleic acid molecule designated ATCC No. PTA-2104.