Claims for Patent: 7,439,230

Summary for Patent: 7,439,230

Title:	Methods of treatment using CTLA4 mutant 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.
Inventor(s):	Peach; Robert J. (San Diego, CA), Naemura; Joseph R. (Bellevue, WA), Linsley; Peter S. (Seattle, WA), Bajorath; Jurgen (Lynwood, WA)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:	10/980,742
Patent Claims:	1. A method for treating transplant rejection in a subject comprising administering to the subject a CTLA4 mutant molecule, wherein the CTLA4 mutant molecule binds CD80 and/or CD86 and comprises the 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, or a portion thereof that binds CD80 and/or CD86, wherein in the extracellular domain or portion thereof 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 inhibiting graft versus host disease in a subject which comprises administering to the subject a CTLA4 mutant molecule and a ligand reactive with IL-4, 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. The method of claim 2, 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. 4. A method for treating transplant rejection 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. 5. A method for treating transplant rejection 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. 6. The method of claim 4, wherein the CTLA4 mutant molecule further comprises an amino acid sequence which alters the solubility or affinity of the CTLA4 mutant molecule. 7. The method of claim 6, wherein the amino acid sequence which alters the solubility or affinity comprises an immunoglobulin. 8. The method of claim 7, wherein the immunoglobulin is an immunoglobulin constant region or portion thereof. 9. The method of claim 8, wherein the immunoglobulin constant region or portion thereof is mutated to reduce effector function. 10. The method of claim 8, wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule. 11. The method of claim 9, wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule. 12. A method for treating transplant rejection 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. 13. A method for treating transplant rejection in a subject comprising administering to the subject a CTLA4 mutant molecule, wherein the CTLA4 mutant molecule consists of: (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. 14. A method for treating transplant rejection in a subject comprising administering to the subject the CTLA4 mutant molecule encoded by the nucleic acid molecule designated ATCC No. PTA-2104. 15. The method of claims 4, 8, 9, 10, 11, 12, or 14 wherein the transplant rejection is selected from the group consisting of solid organ and/or tissue transplant rejection, allo- or xenograft acute or chronic rejection, tissue or cell allo- or xenograft rejection, skin transplant rejection, islet transplant rejection, muscle transplant rejection, hepatocyte transplant rejection, and neuron transplant rejection. 16. The method of claim 15, wherein the CTLA4 mutant molecule is administered concomitantly or in sequence with one or more agents selected from the group consisting of corticosteroids, azathioprine, tacrolimus, basiliximab, cyclosporin A, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, fingolimod; cyclophosphamide; methotrexate; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine, and CTLA4/CD28-lg.

Details for Patent 7,439,230

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Novartis Pharmaceuticals Corporation	SIMULECT	basiliximab	For Injection	103764	05/12/1998		2020-05-26
Novartis Pharmaceuticals Corporation	SIMULECT	basiliximab	For Injection	103764	01/02/2003		2020-05-26