METHODS AND COMPOSITIONS FOR USE IN TREATMENT OF PATIENTS WITH AUTOANTIBODY POSITIVE DISEASE

• US 20090148462A1
• Filed: 06/06/2008
• Published: 06/11/2009
• Est. Priority Date: 10/13/2005
• Status: Active Grant

• Current Assignee: Human Genome Sciences Incorporated (GSK plc)
• Original Assignee: Human Genome Sciences Incorporated (GSK plc)
• Inventors: Zhong, Zhenshao, Odenheimer, Daniel, Perkins, Melissa D., Chevrier, Marc, Freimuth, William W.
• Granted Patent: US 9,168,286 B2
• Time in Patent Office: Days
• US Class Current: 424/158.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• 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 38/19 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 14/70575 NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154 NGF C07K14/48, TNF C07K14/525
• 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 16/2887 against CD20
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

The present invention relates to methods and compositions for use in treatment of patients with autoantibody positive disease. In a specific embodiment, the present invention relates to a method of treating a patient that has an ANA titer of 1:80 or greater and/or greater than or equal to 30 IU/ml of anti-dsDNA antibodies in his/her blood plasma or serum comprising administering a therapeutically effective amount of an immunomodulatory agent, such as an antagonist of Neutrokine-alpha. Additionally provided is a method of reducing the frequency and/or quantity of corticosteroid administration to patients. In preferred embodiments, the patient has systemic lupus erythematosus. Methods for determining if a lupus patient is responding to medical treatment are also provided.

Claims

1. A method of treating a patient that has an ANA titer ≧

1;

80 or ≧

30 IU/mL of anti-dsDNA antibodies in his/her blood plasma or serum comprising administering a therapeutically effective amount of an antagonist of Neutrokine-alpha.

2. The method of claim 1 wherein the patient has an ANA titer ≧

1;

80 and ≧

30 IU/mL of anti-dsDNA antibodies in his/her blood plasma or serum.

3. The method of claim 1 wherein the antagonist of Neutrokine-alpha is administered in combination with an anti-CD20 antibody.

4. The method of claim 1 which comprises making a determination, prior to administering the antagonist of Neutrokine-alpha, that the patient has an ANA titer ≧

1;

80 or ≧

30 IU/mL of anti-dsDNA antibodies in his/her blood plasma or serum.

5. The method of claim 4 wherein the determination is made on the basis of the patient'"'"'s medical record.

6. The method of claim 4 wherein the determination is made on the basis of laboratory tests.

7. The method of claim 1 wherein the antagonist of Neutrokine-alpha is an anti-Neutrokine-alpha antibody.

8. The method of claim 1 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of TACI (SEQ ID NO:

6).

9. The method of claim 1 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of BCMA (SEQ ID NO:

8).

10. The method of claim 1 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of BAFF-R (SEQ ID NO:

10) or a variant of the BAFF-R Neutrokine-alpha binding domain having the amino acid sequence of amino acid residues 2-70 of SEQ ID NO;

26.

11. The method of claim 1 wherein the antagonist of Neutrokine-alpha is a Neutrokine-alpha-binding peptide, a peptibody, a Neutrokine-alpha protein variant or an anti-Neutrokine-alpha receptor antibody.

12. The method of claim 11 wherein the Neutrokine-alpha protein variant acts as a dominant negative.

13. The method of claim 1 wherein the patient has an autoimmune disease.

14. The method of claim 13 wherein the autoimmune disease is systemic lupus erythematosus (SLE).

15. The method of claim 14 wherein the antagonist of Neutrokine-alpha is administered in combination with an anti-CD20 antibody.

16. The method of claim 13 wherein the autoimmune disease is rheumatoid arthritis, Sjö

gren'"'"'s syndrome, scleroderma, polymyositis, dermatomyositis, Felty'"'"'s syndrome, mixed connective tissue disease, Raynaud'"'"'s syndrome, or juvenile chronic arthritis.

17. The method of claim 7 wherein the antibody comprises the amino acid sequences of a set of VH and VL domains selected from the group consisting of:

(a) the VH domain and the VL domain of SEQ ID NO;

13;

(b) the VH domain and the VL domain of SEQ ID NO;

14;

(c) the VH domain and the VL domain of SEQ ID NO;

15;

(d) the VH domain and the VL domain of SEQ ID NO;

16;

(e) the VH domain and the VL domain of SEQ ID NO;

17;

(f) the VH domain and the VL domain of SEQ ID NO;

18;

(g) the VH domain of SEQ ID NO;

19 and the VL domain of SEQ ID NO;

20; and

(h) the VH domain of SEQ ID NO;

21 and the VL domain of SEQ ID NO;

22.

18. A method of treating a patient with systemic lupus erythematosus comprising:

(a) making a determination that the patient has an ANA titer ≧

1;

80 or ≧

30 IU/mL of anti-dsDNA antibodies in his/her blood plasma or serum; and

(b) administering a therapeutically effective amount of an antagonist of Neutrokine-alpha to said patient after making said determination.

19. The method of claim 18 wherein the patient has ANA titer ≧

1;

80 and ≧

30 IU/mL of anti-dsDNA antibodies in his/her blood plasma or serum.

20. The method of claim 18 wherein the antagonist of Neutrokine-alpha is administered in combination with an anti-CD20 antibody.

21. The method of claim 18 which also comprises making a determination, prior to administering the antagonist of Neutrokine-alpha, that the patient has at least one characteristic selected from the group consisting of:

(a) a SELENA SLEDAI score ≧

6.

(b) a depressed level of C3 complement factor in his/her blood plasma or serum;

(c) a depressed level of C4 complement factor in his/her blood plasma or serum;

(d) the patient is receiving ≧

7.5 milligrams/day of prednisone; and

(e) the patient is receiving or had previously received immunosuppressant therapy for the treatment of lupus-related symptoms.

22. The method of claim 21 which comprises making a determination that the patient has a SELENA SLEDAI score greater ≧

6 prior to administering the antagonist of Neutrokine-alpha.

23. The method of claim 21 which comprises making a determination that the patient has less than 90 milligrams/deciliter of C3 complement factor in his/her blood plasma or serum prior to administering the antagonist of Neutrokine-alpha.

24. The method of claim 21 which comprises making a determination that the patient has less than 16 milligrams/deciliter of C4 complement factor in his/her blood plasma or serum prior to administering the antagonist of Neutrokine-alpha.

25. The method of claim 21 which comprises making a determination that the patient is receiving ≧

7.5 milligrams/day of prednisone prior to administering the antagonist of Neutrokine-alpha.

26. The method of claim 21 which comprises making a determination that the patient is receiving or had previously received immunosuppressant therapy for the treatment of lupus-related symptoms prior to administering the antagonist of Neutrokine-alpha.

27. The method of claim 18 wherein the determination is made on the basis of the patient'"'"'s medical record.

28. The method of claim 18 wherein the determination is made on the basis of laboratory tests.

29. The method of claim 18 wherein the antagonist of Neutrokine-alpha is an anti-Neutrokine-alpha antibody.

30. The method of claim 18 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of TACI (SEQ ID NO:

6).

31. The method of claim 18 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of BCMA (SEQ ID NO:

8).

32. The method of claim 18 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of BAFF-R (SEQ ID NO:

10) or a variant of the BAFF-R Neutrokine-alpha binding domain having the amino acid sequence of amino acid residues 2-70 of SEQ ID NO;

26.

33. The method of claim 18 wherein the antagonist of Neutrokine-alpha is a Neutrokine-alpha-binding peptide, a peptibody, a Neutrokine-alpha protein variant or an anti-Neutrokine-alpha receptor antibody.

34. The method of claim 33 wherein the Neutrokine-alpha protein variant acts as a dominant negative.

35. A method of reducing the frequency or quantity of corticosteroid administered to a patient with systemic lupus erythematosus comprising administering a therapeutically effective amount of an antagonist of Neutrokine-alpha to said patient.

36. The method of claim 35 which also comprises making a determination, prior to administering the antagonist of Neutrokine-alpha, that the patient has at least one characteristic selected from the group consisting of:

(a) an ANA titer ≧

1;

80;

(b)≧

30 IU/mL of anti-dsDNA antibodies in his/her blood plasma or serum;

(c) a SELENA SLEDAI score ≧

6;

(d) a depressed level of C3 complement factor in his/her blood plasma or serum;

(e) a depressed level of C4 complement factor in his/her blood plasma or serum;

(f) the patient is receiving ≧

7.5 milligrams/day of prednisone; and

(g) the patient is receiving or had previously received immunosuppressant therapy for the treatment of lupus-related symptoms.

37. The method of claim 36 which comprises making a determination that the patient has an ANA titer ≧

1;

80.

38. The method of claim 36 which comprises making a determination that the patient has ≧

30 IU/mL of anti-dsDNA antibodies in his/her blood plasma or serum.

39. The method of claim 36 which comprises making a determination that the patient has an ANA titer ≧

1;

80 and ≧

30 IU/mL of anti-dsDNA antibodies in his/her blood plasma or serum.

40. The method of claim 36 which comprises making a determination that the patient has a SELENA SLEDAI score greater ≧

6 prior to administering the antagonist of Neutrokine-alpha.

41. The method of claim 36 which comprises making a determination that the patient has less than 90 milligrams/deciliter of C3 complement factor in his/her blood plasma or serum prior to administering the antagonist of Neutrokine-alpha.

42. The method of claim 36 which comprises making a determination that the patient has less than 16 milligrams/deciliter of C4 complement factor in his/her blood plasma or serum prior to administering the antagonist of Neutrokine-alpha.

43. The method of claim 36 which comprises making a determination that the patient is receiving ≧

7.5 milligrams/day of prednisone prior to administering the antagonist of Neutrokine-alpha.

44. The method of claim 36 which comprises making a determination that the patient is receiving or had previously received immunosuppressant therapy for the treatment of lupus-related symptoms prior to administering the antagonist of Neutrokine-alpha.

45. The method of claim 36 wherein the determination is made on the basis of the patient'"'"'s medical record.

46. The method of claim 36 wherein the determination is made on the basis of laboratory tests.

47. The method of claim 35 wherein the antagonist of Neutrokine-alpha is an anti-Neutrokine-alpha antibody.

48. The method of claim 35 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of TACI (SEQ ID NO:

6).

49. The method of claim 35 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of BCMA (SEQ ID NO:

8).

50. The method of claim 35 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of BAFF-R (SEQ ID NO:

10) or a variant of the BAFF-R Neutrokine-alpha binding domain having the amino acid sequence of amino acid residues 2-70 of SEQ ID NO;

26.

51. The method of claim 35 wherein the antagonist of Neutrokine-alpha is a Neutrokine-alpha-binding peptide, a peptibody, a Neutrokine-alpha protein variant or an anti-Neutrokine-alpha receptor antibody.

52. The method of claim 51 wherein the Neutrokine-alpha protein variant acts as a dominant negative.

53. The method of claim 35 wherein the corticosteroid is selected from the group consisting of prednisone, prednisolone, hydrocortisone, methylprednisolone and dexamethasone.

54. The method of claim 35 wherein the corticosteroid is prednisone.

55. The method of claim 54 wherein the quantity of prednisone administered to a patient is reduced by at least 25% to <

7.5 milligrams/day.

56. A method of determining if a lupus patient is responding to medical treatment comprising:

(a) determining the patient'"'"'s SELENA SLEDAI, BILAG and PGA score prior to administration of medical treatment;

(b) administering the medical treatment; and

(c) determining the patient'"'"'s SELENA SLEDAI, BILAG and PGA score following the administration of the medical treatment;

wherein the patient is considered to have responded to medical treatment if the SELENA SLEDAI score determined in step (c) is 4 or more points less than the SELENA SLEDAI score determined in step (a), the BILAG index score determined in step (c) does not include a new BILAG A organ domain score or 2 new BILAG B organ domain scores compared to the BILAG score determined in step (a), and the PGA score determined in step (c) is <

0.3 point higher than the PGA score determined in step (a).

57. The method of claim 56 wherein the medical treatment is a pharmaceutical composition comprising an antagonist of Neutrokine-alpha.

58. The method of claim 56 wherein the antagonist of Neutrokine-alpha is an anti-Neutrokine-alpha antibody.

59. The method of claim 56wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of TACI (SEQ ID NO:

6).

60. The method of claim 56 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of BCMA (SEQ ID NO:

8).

61. The method of claim 56 wherein the antagonist of Neutrokine-alpha is a protein comprising the Neutrokine-alpha binding domain of BAFF-R (SEQ ID NO:

10) or a variant of the BAFF-R Neutrokine-alpha binding domain having the amino acid sequence of amino acid residues 2-70 of SEQ ID NO;

26.

62. The method of claim 56 wherein the antagonist of Neutrokine-alpha is a Neutrokine-alpha-binding peptide, a peptibody, a Neutrokine-alpha protein variant or an anti-Neutrokine-alpha receptor antibody.

63. The method of claim 62 wherein the Neutrokine-alpha protein variant acts as a dominant negative.

64. An aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody, a buffer in an amount from about 5 mM to about 50 mM, NaCl in an amount from about 150 mM to about 500 mM, a surfactant in an amount from about 0.003% to about 0.05%, with a pH from about 5.5 to about 6.5.

65. The formulation of claim 64 wherein the antibody is a human IgG1/λ

antibody, the buffer is 10 mM histidine, the surfactant is polysorbate 80 in an amount of 0.01% w/v, the NaCl is 150 mM and wherein the formulation has a pH of 6.0.

66. The formulation of claim 65 which is stable at a temperature of about 2-8°

C. for at least one year.

67. The formulation of claim 65 which is stable at a temperature of about 2-8°

C. for at least two years.

68. The formulation of claim 65 wherein the antibody is present in an amount of 100 mg/ml.

69. The aqueous pharmaceutical formulation of claim 64 comprising 100 mg/ml IgG1/λ

antibody, 0.74 mg/ml L-histidine, 1.1 mg/ml L-histidine monohydrochloride, 8.8 mg/ml NaCl and 0.1 mg/ml polysorbate 80 and wherein the formulation has a pH of 6.0.