Methods for treating immune system diseases using a soluble CTLA4 molecule
The present invention relates to compositions and methods for treating rheumatic disease by administering to a subject, soluble CTLA4 molecules that block endogenous B7 molecules from binding their ligands.
1. A method of treating a subject having rheumatoid arthritis, wherein the subject has failed at least one Disease Modifying Antirheumatic Drug (DMARD), comprising administering an effective amount of a soluble CTLA4 fusion molecule comprising an extracellular domain of a CTLA4 molecule, wherein the extracellular domain of the CTLA4 molecule comprises the amino acids shown in SEQ ID NO: 17 beginning with methionine at position +27 or with alanine at position +26 and ending with aspartic acid at position +150.
2. The method of claim 1 , wherein the DMARD is methotrexate, cyclophosphamide, azathioprine, cyclosporin A, or a tumor necrosis factor-alpha (TNFα) blocker or antagonist.
3. The method of claim 1 or 2 , for reducing a symptom of rheumatoid arthritis.
4. The method of claim 3 , wherein the symptom is selected from the group consisting of joint swelling, joint tenderness, inflammation, morning stiffness, pain, structural damage, an elevated level of serum C-reactive protein, an elevated level of soluble IL-2r, an elevated level of soluble ICAM-1, an elevated level of soluble E-selectin and an elevated erythrocyte sedimentation rate.
5. The method of claims 1 or 2 , wherein an effective amount of the soluble CTLA4 fusion molecule is 10 mg/kg weight of the subject.
6. The method of claims 1 or 2 , wherein the effective amount of the soluble CTLA4 fusion molecule is 0.5 mg/kg weight of the subject.
7. The method of claims 1 or 2 , wherein the effective amount of the soluble CTLA4 fusion molecule is 2 mg/kg weight of the subject.
8. The method of claim 5 , wherein the effective amount of the soluble CTLA4 fusion molecule is administered intravenously over 1 hour.
9. The method of claim 1 , wherein the effective amount of the soluble CTLA4 fusion molecule is 0.5 to 10 mg/kg weight of a subject.
10. The method of claim 1 , wherein the effective amount of the soluble CTLA4 fusion molecule is 0.1 to 20 mg/kg weight of a subject.
11. The method of claim 1 , wherein administration is effected locally or systemically.
12. The method of claim 11 , wherein administration is selected from the group consisting of intravenous, intramuscular, subcutaneous, implantable pump, continuous infusion, liposomal and oral administration.
13. The method of claim 1 , wherein the extracellular domain of the CTLA4 molecule is joined to a non-CTLA4 molecule.
14. The method of 13 , wherein the non- CTLA4 molecule comprises an amino acid sequence which alters the solubility or affinity of the soluble CTLA4 fusion molecule.
15. The method of claim 14 , wherein the amino acid sequence which alters the solubility or affinity comprises an immunoglobulin moiety.
16. The method of claim 15 , wherein the immunoglobulin moiety is an immunoglobulin constant region or portion thereof.
17. The method of claim 16 , wherein the immunoglobulin constant region or portion thereof is mutated to reduce effector function.
18. The method of claim 16 , wherein the immunoglobulin constant region or portion thereof is mutated to reduce effector function.
19. The method of claim 16 , wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule.
20. The method of claim 17 , wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule.
21. A method for reducing or preventing structural damage in a subject having a rheumatic disease comprising administering an effective amount of a soluble CTLA4 fusion molecule comprising an extracellular domain of a CTLA4 molecule, wherein the extracellular domain of the CTLA4 molecule comprises the amino acids shown in SEQ ID NO: 17 beginning with methionine at position +27 or with alanine at position +26 and ending with aspartic acid at position +150.
22. The method of claim 21 , wherein the structural damage is bone or joint erosion.
23. The method of claim 21 , wherein an effective amount of the soluble CTLA4 fusion molecule is 0.5 and 20 mg/kg weight of the subject.
24. The method of claim 5 comprising administering to a subject a soluble CTLA4 fusion molecule encoded by a nucleic acid molecule designated ATCC No. 68629.
25. The method of claim 9 or 10 comprising administering to a subject a soluble CTLA4 fusion molecule encoded by a nucleic acid molecule designated ATCC No. 68629.
26. The method of claim 5 comprising administering to a subject a soluble CTLA4 fusion molecule, wherein said soluble CTLA4 fusion molecule has the amino acid sequence of a CTLA4Ig fusion protein expressed by the cell deposited as ATCC CRL-10762.
27. The method of claims 1 , wherein administration of the effective amount of the soluble CTLA4 fusion molecule comprises intravenous infusion on days 1, 15, 29 and 57.
28. The method of claim 1 , wherein administration of the soluble CTLA4 fusion molecule improves ACR 20, 50 and/or 70 response rates.
29. The method of claim 1 , wherein the soluble CTLA4 fusion molecule is CTLA4Ig shown in SEQ ID NO: 19 beginning with methionine at position +27 or with alanine at position +26 and ending with lysine at position +383.
30. The method of claim 1 wherein the subject is selected from the group consisting of human, monkey, ape, dog, cat, cow, horse, rabbit, mouse, and rat.
31. The method of claim 21 wherein the rheumatic disease is rheumatoid arthritis.