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. The method of treating an autoimmune disease in a subject comprising administering to the subject a CTLA4 molecule, wherein the CTLA4 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: 8, or
(b) an amino acid sequence beginning with alanine at position 26 and ending with aspartic acid at position 150 of SEQ ID NO: 8, and wherein said autoimmune disease is selected from the group consisting of lupus, lupus erythematosus, and lupus nephritis.
2. The method of claim 1 further comprising an amino acid sequence which alters the solubility or affinity of the CTLA4 mutant molecule.
3. The method of claim 2 , wherein the amino acid sequence which alters the solubility or affinity comprises an immunoglobulin.
4. The method of claim 3 , wherein the immunoglobulin is an immunoglobulin constant region or portion thereof.
5. The method of claim 4 , wherein the immunoglobulin constant region or portion thereof is mutated to reduce effector function.
6. The method of claim 4 , wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule.
7. The method of claim 5 , wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule.
8. The method of claim 1 , 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: 8, or
(b) an amino acid sequence beginning with alanine at position 26 and ending with lysine at position 383 of SEQ ID NO: 8.