Methods for protecting allogeneic islet transplant using soluble CTLA4 mutant molecules

• US 7,304,033 B2
• Filed: 05/23/2002
• Issued: 12/04/2007
• Est. Priority Date: 05/23/2001
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Linsley, Peter S., Bajorath, Jurgen, Larsen, Christian P., Adams, Andrew B., Naemura, Joseph Roy, Peach, Robert J., Pearson, Thomas C.
• Primary Examiner(s): Gambel; Phillip
• Assistant Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US10/155,514
• Publication Number:
  US 20030022836A1
• Time in Patent Office: 2,021 Days
• Field of Search: 424/134.1, 424/377, 530/387.3
• 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 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 37/02 Immunomodulators
• 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 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C07K 14/70521 : CD28, CD152
• CPC Class Codes: C07K 16/2866 : against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The present invention is a method of inhibiting islet cell transplant rejection, particularly to treat diabetes, such as type-1 and type-2 diabetes, by administering to a subject an effective amount of a soluble CTLA4 mutant molecule. One example of a soluble CTLA4 mutant molecule is L104EA29YIg.

Claims

1. A method for inhibiting islet cell transplant rejection in a subject, comprising administering to the subject an effective amount of a CTLA4 molecule comprising a mutated extracellular domain comprising an amino acid sequence beginning with alanine at position 26 and ending with aspartic acid at position 150 as shown in SEQ ID NO:

6, or beginning with methionine at position 27 and ending with aspartic acid at position 150 as shown in SEQ ID NO;

6.

2. A method for treating diabetes by inhibiting islet cell transplant rejection in a subject by the method of claim 1.

3. The method of claim 1, wherein the islet cells are encapsulated prior to administration to the subject.

4. The method of claim 1, further comprising administering to the subject an effective amount of at least one of an immunosuppressive agent, an immunomodulatory compound, and an anti-inflammatory agent, wherein the CTLA4 molecule and at least one of an immunosuppressive agent, an immunomodulatory compound and an anti-inflammatory agent are to be administered concomitantly or in sequence.

5. The method of claim 4, wherein the immunosuppressive agent is (i) rapamycin (sirolimus) or its derivative 40-O-(2-hydroxy)ethyl-rapamycin, (ii) anti-human IL-2R mAb, or (iii) a combination of (i) and (ii).

6. The method of claim 4, wherein the immunosuppressive agent is a cyclosporin, tacrolimus, prednisone, azathioprine, methotrexate, infliximab, hydroxychloroquine, sulphasalazopryine, etanercept, anakinra, basiliximab, chloroquine, cyclophosphamide, cytoxan, 15-deoxyspergualine, D-penicillamine, glatiramer acetate, FTY720, horse anti-human thymocyte globulin (ATGAM), humanized anti-TAC (HAT), interferon beta-1a, interferon beta-1b, leflunomide, lymphocyte immune globulin, methoxsalen, mitoxantrone hydrochloride, mycophenolic acid, mycophenolate mofetil, mizoribine, rabbit anti-human thymocyte globulin, Rho (D) immune globulin, sirolimus (rapamycin), sulfasalzine, thalidomide, soluble gp39, soluble CD29, soluble CD40, soluble CD80, soluble CD86, soluble CD28, soluble CD56, soluble Thy-1, soluble CD3, soluble TCR, soluble VLA-4, soluble VCAM-1, soluble LECAM-1, soluble ELAM-1, soluble CD44, antibodies to gp39, antibodies to CD40, antibodies to B7-1 or B7-2, antibodies to CD28, antibodies to LFA-1, antibodies to LFA-2, antibodies to IL-2, antibodies to IL 12, antibodies to IFN-gamma, antibodies to CD2, antibodies to CD48, antibodies to any ICAM, antibodies to CTLA4, antibodies to Thy-1, antibodies to CD56, antibodies to CD3, antibodies to CD29, antibodies to TCR, antibodies to VLA-4, antibodies to VCAM-1, antibodies to LECAM-1, antibodies to ELAM-1, antibodies to CD44, monoclonal antibodies to OX40, or 4-1BB CTLA4/CD28-1g, anti-human IL-2R mAbs, 40-0(2hydroxy)ethyl-rapamycin, soluble CD80 deposited as ATCC 68627, an antibody to any of ICAM-1, ICAM-2 and ICAM-3, or a monoclonal antibody to any of MHC, CD2, CD3, CD4, CD11a/CD18, CD7, CD25, CD27, B7, CD40, CD45, CD58, CD137, ICOS, or CD150 (SLAM).

7. The method of claim 4, wherein administration is by intravenous injection, intramuscular injection, subcutaneous injection, implantable pump, continuous infusion, gene therapy, liposomes or oral administration.

8. The method of claim 1, wherein the subject is a human, non-human primate, rabbit, sheep, rat, dog, cat, pig, or mouse.

9. The method of claim 1 further comprising administering T cell depleted bone marrow cells to the subject.

10. The method of claim 1, wherein the subject is being transplanted with islet cells before, or after, administration of the CTLA4 molecule.

11. The method of claim 2, wherein diabetes is type 1 diabetes or type 2 diabetes.

12. The method of claim 1, wherein the mutated extracellular domain is fused to a non-CTLA4 moiety.

13. The method of claim 12, wherein the non-CTLA4 moiety comprises an immunoglobulin moiety.

14. The method of claim 13, wherein the immunoglobulin moiety is an immunoglobulin constant region or portion thereof.

15. The method of claim 14, wherein the immunoglobulin constant region or portion thereof comprises one or more mutations to reduce effector function.

16. The method of claims 14 or 15, wherein the immunoglobulin constant region comprises the hinge, CH2 and CH3 regions of an immunoglobulin molecule.

17. The method of claim 14, wherein the immunoglobulin constant region or portion thereof is a human or monkey immunoglobulin constant region.

19. The method of claims 1 or 18 further comprising administering to the subject an effective amount of an immunosuppressive agent.

20. The method of claim 19, wherein the immunosuppressive agent is glucocorticoid-free.

21. The method of claim 19, wherein the immunosuppressive agent is calcineurin inhibitor-free.

22. The method of claim 19, wherein the immunosuppressive agent comprises (i) rapamycin (sirolimus) or its derivative 40-O-(2-hydroxy)ethyl-rapamycin, (ii) anti-IL-2R monoclonal antibody, or (iii) a combination of (i) and (ii).

23. The method of claim 22, wherein the anti-IL-2R monoclonal antibody is basiliximab.

31. The method of claims 1 or 4, wherein the CTLA4 molecule is encoded by DNA deposited as ATCC number PTA 2104.

32. The method of claims 1 or 4, wherein the CTLA4 molecule is expressed by DNA deposited as ATCC number PTA 2104.

18. A method for inhibiting islet cell transplant rejection in a subject, comprising administering to the subject an effective amount of a soluble CTLA4 mutant molecule, wherein the soluble CTLA4 mutant molecule comprises an amino acid sequence as shown in SEQ ID NO:

6 beginning with alanine at position 26 and ending with lysine at position 383, or beginning with methionine at position 27 and ending with lysine at position 383.

24. A method for inhibiting islet cell transplant rejection in a subject, comprising administering to the subject an effective amount of a soluble CTLA4 mutant molecule encoded by DNA deposited as ATCC number PTA-2104.

26. The method of claims 24 or 25, further comprising administering to the subject an effective amount of an immunosuppressive agent.

27. The method of claim 26, wherein the immunosuppressive agent is glucocorticoid-free.

28. The method of claim 26, wherein the immunosuppressive agent is calcineurin inhibitor-free.

29. The method of claim 26, wherein the immunosuppressive agent comprises (i) rapamycin (sirolimus) or its derivative 40-O-(2-hydroxy)ethyl-rapamycin, (ii) an anti-IL-2R monoclonal antibody, or (iii) a combination of (i) and (ii).

30. The method of claim 29, wherein the anti-IL-2R monoclonal antibody is basiliximab.

25. A method for inhibifmg islet cell transplant rejection in a subject, comprising administering to the subject an effective amount of a soluble CTLA4 mutant molecule expressed by DNA deposited as ATCC number PTA-2104.