Methods for treating immune system diseases using a soluble CTLA4 molecule

• US 7,455,835 B2
• Filed: 07/02/2001
• Issued: 11/25/2008
• Est. Priority Date: 07/03/2000
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Linsley, Peter S., Bajorath, Jurgen, Becker, Jean-Claude, Hagerty, David, Peach, Robert James, Naemura, Joseph Roy, Cohen, Robert, Carr, Suzette
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US09/898,195
• Publication Number:
  US 20030083246A1
• Time in Patent Office: 2,703 Days
• Field of Search: 424/185.1, 424/192.1, 530/351
• US Class Current: 424/134.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07K 14/70521 : CD28, CD152
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide

Abstract

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.

Claims

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.

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.

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.

31. The method of claim 21 wherein the rheumatic disease is rheumatoid arthritis.