Antagonists of IL-6 to prevent or treat thrombosis

• US 8,252,286 B2
• Filed: 11/25/2008
• Issued: 08/28/2012
• Est. Priority Date: 05/21/2007
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Seattle Biopharmaceuticals, Inc.)
• Inventors: Smith, Jeffrey T. L.
• Primary Examiner(s): Bunner, Bridget E
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US12/323,194
• Publication Number:
  US 20090291089A1
• Time in Patent Office: 1,372 Days
• Field of Search: None
• 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 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 reducing the risk of hypercoagulation or thrombosis in a subject having an elevated IL-6 level and an elevated D-dimer level by reducing the level of serum D-dimer in said subject, comprising administering to the subject an amount of an IL-6 antagonist, wherein said IL-6 antagonist is an antibody or antibody fragment that specifically binds human IL-6 and which is administered in an amount effective to reduce the level of serum D-dimer thereby reducing the risk of hypercoagulation or thrombosis in said subject.

2. The method of claim 1 wherein said subject also has an elevated C-reactive protein (CRP) level prior to treatment.

3. The method of claim 1 wherein said method further comprises the administration of at least one statin or anti-coagulant.

4. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment is administered to the subject with a frequency at most once per period of approximately four weeks.

5. The method of claim 1, wherein the subject'"'"'s coagulation profile is assayed after treatment.

6. The method of claim 1, wherein the subject'"'"'s coagulation profile is assayed before treatment.

7. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment has an elimination half-life of at least about 22 days.

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

9. The method of claim 1, wherein the subject'"'"'s coagulation profile is assessed before or after treatment by measurement of the subject'"'"'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.

10. The method of claim 1, further comprising measuring the subject'"'"'s international normalized ratio (INR) prior to administration of the anti-IL-6 antibody or antibody fragment and administering to the subject said anti-IL-6 antibody if the subject'"'"'s INR is less than about 0.9.

11. The method of claim 1, wherein the subject'"'"'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 subject said anti-IL-6 antibody.

12. The method of claim 1 wherein the subject treated has cancer.

13. The method of claim 1 wherein the subject being treated is undergoing chemotherapy.

14. The method of claim 1, further comprising measuring the level of IL-6 in the subject prior to treatment.

15. The method of claim 1, further comprising measuring the level of C-reactive protein in the subject prior to treatment.

16. The method of claim 5, wherein the subject'"'"'s coagulation profile is assayed by a method comprising measuring the concentration of D-dimer in the subject'"'"'s serum.

17. The method of claim 6, wherein the subject'"'"'s coagulation profile is assayed by a method comprising measuring the concentration of D-dimer in the subject'"'"'s serum.

18. The method of claim 1, wherein said antibody or antibody fragment inhibits the interaction of IL-6 with gp130.

19. The method of claim 1, wherein said antibody or antibody fragment inhibits the interaction of IL-6 with IL-R1.

20. The method of claim 1, wherein said antibody or antibody fragment inhibits the interaction of IL-6 with gp130 and IL-6R1.

21. The method of claim 1, wherein said antibody or antibody fragment neutralizes IL-6 in vivo.

22. The method of claim 1, wherein said antibody or antibody fragment binds to IL-6 with a dissociation constant (K_D) of less than or equal to 5×

10<sup>−

7</sup>, 10<sup>−

7</sup>, 5×

10<sup>−

8</sup>, 10<sup>−

8</sup>, 5×

10<sup>−

9</sup>, 10<sup>−

9</sup>, 5×

10<sup>−

10</sup>, 10<sup>−

10</sup>, 5×

10<sup>−

11</sup>, 10<sup>−

11</sup>, 5×

10<sup>−

12</sup>, 10<sup>−

12</sup>, 5×

10<sup>−

13</sup>, 10<sup>−

13</sup>, 5×

10<sup>−

14</sup>, 10<sup>−

14</sup>, 5×

10<sup>−

15</sup> or 10<sup>−

15</sup>.

23. The method of claim 1, wherein said antibody or antibody fragment binds to IL-6 with a dissociation constant of less than or equal to 5×

10<sup>−

10</sup>.

24. The method of claim 1, wherein said antibody or antibody fragment possesses a binding affinity (Kd) less than 50 picomolar.

25. The method of claim 1, wherein said antibody or antibody fragment possesses a K_off value less than or equal to 10⁻

4 S<sup>−

1</sup>.