Antagonists of IL-6 to prevent or treat Thrombosis

• US 20090291089A1
• Filed: 11/25/2008
• Published: 11/26/2009
• Est. Priority Date: 05/21/2007
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Smith, Jeffrey T.L.
• Granted Patent: US 8,252,286 B2
• Time in Patent Office: Days
• US Class Current: 424/158.1
• 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 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07K 16/241 Tumor Necrosis Factors
• CPC Class Codes: C07K 16/248 IL-6
• CPC Class Codes: C07K 16/461 Igs containing Ig-regions, -domains or -residues form different species
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• 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 2317/76 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
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention is directed to therapeutic methods using IL-6 antagonists such as antibodies and fragments thereof having binding specificity for IL-6 to prevent or treat thrombosis in diseases associated with abnormal blood coagulation or fibrinolysis. In preferred embodiments these patients will comprise those exhibiting elevated D-dimer or other coagulation cascade related proteins and optionally will further exhibit elevated C reactive protein prior to treatment. The subject therapies also may include the administration of other actives such as chemotherapeutics, anti-coagulants, statins, et al.

Claims

1. A method of treating a patient having a disease or condition associated with hypercoagulation, comprising administering to the patient an IL-6 antagonist, whereby the patient'"'"'s coagulation profile is improved or restored to normal, and monitoring the patient to assess coagulation profile.

2. The method of claim 1 wherein the patient has elevated serum D-dimer levels prior to treatment.

3. The method of claim 2 wherein said patient also has elevated C-reactive protein (CRP) levels prior to treatment.

4. The method of claim 3 wherein said method further comprises the administration of at least one statin.

9. The method of claim 1, wherein the antagonist comprises an anti-IL-6 antibody or antibody fragment.

10. The method of claim 9, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same linear or conformational epitope(s) and/or competes for binding to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or antibody fragment thereof as an anti-IL-6 antibody selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36.

12. The method of claim 10, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or antibody fragment thereof as an anti-IL-6 antibody selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36.

13. The method of claim 10, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or a fragment thereof as Ab1.

14. The method of claim 10, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same linear or conformational epitopes on an intact IL-6 polypeptide or antibody fragment thereof that is (are) specifically bound by Ab1 and wherein said epitope(s) when ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide includes one or more residues comprised in IL-6 fragments selected from those respectively encompassing amino acid residues 37-51, amino acid residues 70-84, amino acid residues 169-183, amino acid residues 31-45 and/or amino acid residues 58-72.

24. The method of claim 10, wherein the anti-IL-6 antibody or antibody fragment is administered to the patient with a frequency at most once per period of approximately four weeks.

28. The method of claim 24, wherein the patient'"'"'s coagulation profile remains improved for an entire period intervening two consecutive anti-IL-6 antibody administrations.

31. The method of claim 10, wherein the anti-IL-6 antibody or antibody fragment comprises a V_H polypeptide sequence selected from the group consisting of:

SEQ ID NO;

3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555 and SEQ ID NO;

571; and

further comprises a V_L polypeptide sequence selected from the group consisting of;

SEQ ID NO;

2, 20, 21, 37, 53, 69, 85, 101, 119, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554 and SEQ ID NO;

570 or a variant thereof wherein one or more of the framework residues (FR residues) in said V_{H or} V_L polypeptide has been substituted with another amino acid residue resulting in an anti-IL-6 antibody or antibody fragment that specifically binds human IL-6.

32. The method of claim 31, wherein one or more of said FR residues are substituted with an amino acid present at the corresponding site in a parent rabbit anti-IL-6 antibody from which the complementarity determining regions (CDRs) contained in said V_{H or} V_L polypeptides have been derived or by a conservative amino acid substitution.

37. The method of claim 10, wherein the anti-IL-6 antibody or antibody fragment comprises a polypeptide having at least 90% sequence homology to one or more of the polypeptide sequences of SEQ ID NO:

3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555, 571, 2, 20, 21, 37, 53, 69, 85, 101, 119, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, and 570.

38. The method of claim 10, wherein the anti-IL-6 antibody or antibody fragment has an elimination half-life of at least about 22 days.

47. The method of claim 10, wherein the anti-IL-6 antibody or antibody fragment is Ab1 or a fragment thereof.

49. The method of claim 1, further comprising administration of one or more anti-coagulants or statins.

52. The method of claim 1, wherein the patient'"'"'s coagulation profile is assessed by measurement of the patient'"'"'s serum level of one or more of D-dimer, Factor II, Factor V, Factor VIII, Factor IX, Factor XI, Factor XII, F/fibrin degradation products, thrombin-antithrombin III complex, fibrinogen, plasminogen, prothrombin, and von Willebrand factor.

55. The method of claim 1, further comprising:

measuring the patient'"'"'s international normalized ratio (INR) prior to administration of the IL-6 antagonist, and administering to the patient an IL-6 antagonist if the patient'"'"'s INR is less than about 0.9.

57. The method of claim 1 wherein the patient'"'"'s INR is raised to more than approximately 0.9 within 4 weeks of administering to the patient an IL-6 antagonist.

59. The method of claim 1, wherein the patient'"'"'s serum D-dimer level is lowered to less than the upper limit of the normal reference range within 4 weeks of administering to the patient an IL-6 antagonist.

61. The method of claim 1, wherein the patient'"'"'s coagulation profile is measurably improved within about 2 weeks of administration of the IL-6 antagonist.

62. The method of claim 61, wherein the patient'"'"'s coagulation profile remains measurably improved approximately 12 weeks after administering to the patient an IL-6 antagonist.

80. The method of claim 1, wherein the IL-6 antagonist is an anti-IL-6 antibody or fragment thereof comprising the CDRs in the variable heavy region having the sequence in SEQ ID NO:

18 or 19 and the CDRs in the variable light region having the sequence in SEQ ID NO;

20.

81. The method of claim 80, wherein the IL-6 antagonist is an anti-IL-6 antibody or fragment thereof comprising a variable heavy region having the sequence in SEQ ID NO:

18 or 19 and a variable light region having the sequence in SEQ ID NO;

20.

5-8. -8. (canceled)

11. (canceled)

15. (canceled)

16. The method of claim 15, wherein the anti-IL-6 antibody or antibody fragment comprises at least 2 complementarity determining regions (CDRs) in each the variable light and the variable heavy regions which are identical to those contained in Ab1.

17-23. -23. (canceled)

25-27. -27. (canceled)

29. (canceled)

30. (canceled)

33-36. -36. (canceled)

39-46. -46. (canceled)

48. (canceled)

50. (canceled)

51. (canceled)

53. (canceled)

54. (canceled)

56. (canceled)

58. (canceled)

60. (canceled)

63-71. -71. (canceled)

72. A composition comprising an IL-6 antagonist, and a statin.

73. (canceled)

74. A composition comprising an IL-6 antagonist, and an anti-coagulant.

75. (canceled)

76. A composition comprising an IL-6 antagonist, and a chemotherapy agent.

77-79. -79. (canceled)