USE OF B LYMPHOCYTE STIMULATOR PROTEIN ANTAGONISTS TO PROMOTE TRANSPLANTATION TOLERANCE

• US 20110014190A1
• Filed: 02/12/2010
• Published: 01/20/2011
• Est. Priority Date: 02/12/2009
• Status: Abandoned Application

• Current Assignee: Human Genome Sciences Incorporated (GlaxoSmithKline PLC), Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Human Genome Sciences Incorporated (GlaxoSmithKline PLC), Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Noorchashm, Hooman, Migone, Thi-Sau, Cancro, Michael
• Application Number:
  US12/705,551
• Publication Number:
  US 20110014190A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• 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 35/39 Pancreas; Islets of Langerhans Langerhans cells of epidermis A61K35/36
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/2875 against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The invention relates to methods of preventing, treating, ameliorating and otherwise inhibiting organ or transplant rejection in a patient by administering B Lymphocyte Stimulator antagonists. In addition, therapeutic treatment regimens are provided to promote transplant tolerance in a patient following the administration of B Lymphocyte Stimulatorantagonists.

Claims

1. A method of promoting transplantation tolerance in a patient comprising administering to the patient an effective amount of a B Lymphocyte Stimulator antagonist, thereby delaying or inhibiting transplant rejection in the patient.

2. The method of claim 1, wherein the B Lymphocyte Stimulator antagonist is selected from the group consisting of:

(a) a protein comprising the B Lymphocyte Stimulator binding domain of TACI;

(b) a protein comprising the B Lymphocyte Stimulator binding domain of BCMA;

(c) a protein comprising the B Lymphocyte Stimulator binding domain of BAFF-R;

(d) a B Lymphocyte Stimulator-binding peptide;

(e) a B Lymphocyte Stimulator peptibody;

(f) a B Lymphocyte Stimulator protein variant;

(g) an anti-B Lymphocyte Stimulator antibody; and

(h) an anti-B Lymphocyte Stimulator receptor antibody.

3. The method of claim 1, wherein the B Lymphocyte Stimulator antagonist is an anti-B Lymphocyte Stimulator antibody.

4. The method of claim 3, wherein the anti-B Lymphocyte Stimulator antibody binds a protein selected from the group consisting of:

(a) soluble B Lymphocyte Stimulator protein;

(b) membrane-bound B Lymphocyte Stimulator protein;

(c) the amino acid sequence of amino acid residues 1-285 of SEQ ID NO;

2;

(d) the amino acid sequence of amino acid residues 134-285 of SEQ ID NO;

2;

(e) a trimer of (d);

(f) an amino acid sequence that is at least 90% identical to amino acid residues 1-285 of SEQ ID NO;

2, wherein the amino acid sequence stimulates B cell proliferation, differentiation, or survival;

(g) an amino acid sequence that is at least 90% identical to amino acid residues 134-285 of SEQ ID NO;

2, wherein the amino acid sequence stimulates B cell proliferation, differentiation, or survival;

(h) a trimer of (g); and

(i) the amino acid sequence of a fragment of the polypeptide of SEQ ID NO;

2;

wherein the fragment is at least 30 amino acids in length and wherein the fragment is capable of stimulating B cell proliferation, differentiation, or survival.

5. The method of claim 1, wherein the patient receives an organ or tissue transplant comprising an organ or tissue selected from the group consisting of:

(a) heart;

(b) heart valve;

(c) lung;

(d) kidney;

(e) liver;

(f) pancreas;

(g) intestine;

(h) skin;

(i) blood vessels;

(j) bone marrow;

(k) stem cells;

(l) bone; and

(m) islet cells.

6. The method of claim 5, wherein the patient receives an islet cell transplantation to prevent the onset of diabetes or as a treatment of diabetes.

7. The method of claim 1, further comprising the administration of an immunosuppressant agent.

8. The method of claim 7, wherein the immunosuppressant agent is selected from the group consisting of:

(a) Cyclosporine;

(b) Azathioprine;

(c) Rapamycin;

(d) Mycophenolate mofetil;

(e) Mycophenolic acid;

(f) Prednisone;

(g) Sirolimus;

(h) Basiliximab; and

(i) Daclizumab.

9. The method of claim 8, wherein the immunosuppressant agent is Rapamycin.

10. The method of claim 7, wherein the B Lymphocyte Stimulator antagonist is a B Lymphocyte Stimulator antibody.

11. The method of claim 7, wherein the B Lymphocyte Stimulator antagonist is administered before the immunosuppressant agent is administered to the patient.

12. The method of claim 7, wherein the B Lymphocyte Stimulator antagonist is administered after the immunosuppressant agent is administered to the patient.

13. The method of claim 7, wherein the B Lymphocyte Stimulator antagonist is administered at the same time the immunosuppressant agent is administered to the patient.

14. The method of claim 1, wherein the B Lymphocyte Stimulator antagonist is administered to the patient at least once before transplantation.

15. The method of claim 1, wherein the B Lymphocyte Stimulator antagonist is administered to the patient at least once during or after transplantation surgery.

16. The method of claim 14, wherein one or more maintenance doses of the B Lymphocyte Stimulator antagonist are administered to the patient.

17. The method of claim 16, wherein the maintenance dose of the B Lymphocyte Stimulator antagonist is continued for the life of transplant survival.

18. The method of claim 16, wherein the maintenance dose of the B Lymphocyte Stimulator antagonist is reduced over time.

19. The method of claim 16, wherein the maintenance dose of the B Lymphocyte Stimulator antagonist is discontinued subsequent to transplantation.

20. The method of claim 7, wherein the dose of the immunosuppressant agent is reduced over time.

21. The method of claim 7, wherein the dose of the immunosuppressant agent is discontinued subsequent to transplantation.

22. The method of claim 7, wherein the B Lymphocyte Stimulator antagonist is administered on day 1 and day 10 post-transplantation followed by a maintenance dose every week for at least eight weeks, and the immunosuppressant agent is administered on day 0 post-transplantation and then every other day for at least two weeks.

23. The method of claim 22, wherein the maintenance dose is reduced by at least between 5% to 25% every 2 weeks.

24. A method of treating transplant organ or tissue rejection in a patient comprising administering to the patient an effective amount of a B Lymphocyte Stimulator antagonist, thereby inhibiting transplant organ or tissue rejection in the patient.

25. The method of claim 24, wherein the B Lymphocyte Stimulator antagonist is selected from the group consisting of:

(a) a protein comprising the B Lymphocyte Stimulator binding domain of TACI;

(b) a protein comprising the B Lymphocyte Stimulator binding domain of BCMA;

(c) a protein comprising the B Lymphocyte Stimulator binding domain of BAFF-R;

(d) a B Lymphocyte Stimulator-binding peptide;

(e) a B Lymphocyte Stimulator peptibody;

(f) a B Lymphocyte Stimulator protein variant;

(g) an anti-B Lymphocyte Stimulator antibody; and

(h) an anti-B Lymphocyte Stimulator receptor antibody.

26. The method of claim 24, wherein the B Lymphocyte Stimulator antagonist is an anti-B Lymphocyte Stimulator antibody.

27. The method of claim 26, wherein the anti-B Lymphocyte Stimulator antibody binds a protein selected from the group consisting of:

(a) soluble B Lymphocyte Stimulator protein;

(b) membrane-bound B Lymphocyte Stimulator protein;

(c) the amino acid sequence of amino acid residues 1-285 of SEQ ID NO;

2;

(d) the amino acid sequence of amino acid residues 134-285 of SEQ ID NO;

2;

(e) a trimer of (d);

(f) an amino acid sequence that is at least 90% identical to amino acid residues 1-285 of SEQ ID NO;

2, wherein the amino acid sequence stimulates B cell proliferation, differentiation, or survival;

(g) an amino acid sequence that is at least 90% identical to amino acid residues 134-285 of SEQ ID NO;

2, wherein the amino acid sequence stimulates B cell proliferation, differentiation, or survival

(h) a trimer of (g); and

(i) the amino acid sequence of a fragment of the polypeptide of SEQ ID NO;

2;

wherein the fragment is at least 30 amino acids in length and wherein the fragment is capable of stimulating B cell proliferation, differentiation, or survival.

28. The method of claim 24, wherein the organ or tissue comprises an organ or tissue selected from the group consisting of:

(a) heart;

(b) heart valve;

(c) lung;

(d) kidney;

(e) liver;

(f) pancreas;

(g) intestine;

(h) skin;

(i) blood vessels;

(j) bone marrow;

(k) stem cells;

(l) bone; and

(m) islet cells.

29. The method of claim 28, wherein the organ or tissue comprises islet cells, and wherein inhibiting islet cell rejection in the patient prevents the onset of diabetes or is a treatment of diabetes in the patient.

30. The method of claim 24, further comprising the administration of an immunosuppressant agent.

31. The method of claim 30, wherein the immunosuppressant agent is selected from the group consisting of:

(a) Cyclosporine;

(b) Azathioprine;

(c) Rapamycin;

(d) Mycophenolate mofetil;

(e) Mycophenolic acid;

(f) Prednisone;

(g) Sirolimus;

(h) Basiliximab; and

(i) Daclizumab.

32. The method of claim 31, wherein the immunosuppressant agent is Rapamycin.

33. A method of treating transplant organ or tissue rejection in a patient comprising administering, following a diagnosis of transplant organ or tissue rejection, at least one dose of a B Lymphocyte Stimulator antagonist and an immunosuppressant agent to a patient experiencing symptoms of organ or tissue rejection until symptoms of organ or tissue rejection subside in the patient.

34. A method of decreasing antibody titer in a patient who is in need of or has received an organ or tissue transplant comprising administering to the patient an effective amount of a B Lymphocyte Stimulator antagonist, thereby decreasing antibody titer in the patient.

35. The method of claim 34, wherein the B Lymphocyte Stimulator antagonist is selected from the group consisting of:

(a) a protein comprising the B Lymphocyte Stimulator binding domain of TACI;

(b) a protein comprising the B Lymphocyte Stimulator binding domain of BCMA;

(c) a protein comprising the B Lymphocyte Stimulator binding domain of BAFF-R;

(d) a B Lymphocyte Stimulator-binding peptide;

(e) a B Lymphocyte Stimulator peptibody;

(f) a B Lymphocyte Stimulator protein variant;

(g) an anti-B Lymphocyte Stimulator antibody; and

(h) an anti-B Lymphocyte Stimulator receptor antibody.

36. The method of claim 35, wherein the B Lymphocyte Stimulator antagonist is an anti-B Lymphocyte Stimulator antibody.

37. The method of claim 36, wherein the anti-B Lymphocyte Stimulator antibody binds a protein selected from the group consisting of:

(a) soluble B Lymphocyte Stimulator protein;

(b) membrane-bound B Lymphocyte Stimulator protein;

(c) the amino acid sequence of amino acid residues 1-285 of SEQ ID NO;

2;

(d) the amino acid sequence of amino acid residues 134-285 of SEQ ID NO;

2;

(e) a trimer of (d);

(f) an amino acid sequence that is at least 90% identical to amino acid residues 1-285 of SEQ ID NO;

2, wherein the amino acid sequence stimulates B cell proliferation, differentiation, or survival;

(g) an amino acid sequence that is at least 90% identical to amino acid residues 134-285 of SEQ ID NO;

2, wherein the amino acid sequence stimulates B cell proliferation, differentiation, or survival;

(h) a trimer of (g); and

(i) the amino acid sequence of a fragment of the polypeptide of SEQ ID NO;

2;

wherein said fragment is at least 30 amino acids in length and wherein said fragment is capable of stimulating B cell proliferation, differentiation, or survival.

38. The method of claim 34, wherein the organ or tissue transplant comprises an organ or tissue selected from the group consisting of:

(a) heart;

(b) heart valve;

(c) lung;

(d) kidney;

(e) liver;

(f) pancreas;

(g) intestine;

(h) skin;

(i) blood vessels;

(j) bone marrow;

(k) stem cells;

(l) bone; and

(m) islet cells.

39. The method of claim 34, further comprising the administration of an immunosuppressant agent.

40. The method of claim 39, wherein the immunosuppressant agent is selected from the group consisting of:

(a) Cyclosporine;

(b) Azathioprine;

(c) Rapamycin;

(d) Mycophenolate mofetil;

(e) Mycophenolic acid;

(f) Prednisone;

(g) Sirolimus;

(h) Basiliximab; and

(i) Daclizumab.

41. The method of claim 40, wherein the immunosuppressant agent is Rapamycin.

42. The method of claim 39, wherein the B Lymphocyte Stimulator antagonist is a B Lymphocyte Stimulator antibody.

43. The method of claim 39, wherein the B Lymphocyte Stimulator antagonist is administered following a diagnosis of increased antibody titer followed by doses of both the B Lymphocyte Stimulator antagonist and the immunosuppressant agent until antibody titer decreases.