Antagonists of IL-6 to prevent or treat thrombosis
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 cogulation 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.
1. A method of treating a patient having a disease or condition associated with hypercoagulation, wherein the treated patient is a transplant recipient, comprises comprising administering to the patient an interleukin-6 (IL-6) antibody or antibody fragment which contains the variable light chain CDRs of SEQ ID NO: 4, 5 and 6 and the variable heavy chain CDRs of SEQ ID NO: 7, 8 or 120, and 9, 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 said condition 9 is associated with aberrant serum levels 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.
3. The method of claim 1 , wherein the patient's coagulation profile is assessed before or after treatment 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.
4. The method of claim 1 wherein the patient has elevated serum D-dimer levels prior to treatment, and/or elevated C-reactive protein (CRP) levels prior to treatment.
5. The method of claim 1 wherein said method further comprises the administration of at least one statin or anti-coagulant.
6. The method of claim 5 wherein said anti-IL-6 antibody or antibody fragment further comprises a human Fc derived from IgG1, IgG2, IgG3, or IgG4.
7. The method of claim 5 wherein the one or more anti-coagulants are selected from abciximab, acenocoumarol, antithrombin III, argatroban, aspirin, bivalirudin, clopidogrel, dabigatran, dabigatran etexilate, desirudin, dipyridamole, eptifibatide, fondaparinux, heparin, hirudin, idraparinux, lepirudin, low molecular weight heparin, melagatran, phenindione, phenprocoumon, ticlopidine, tirofiban, warfarin, ximelagatran, ximelagatran, or any combination thereof and the one or more statins is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, or any combination thereof.
8. The method of claim 1 wherein the anti-IL-6 antibody or antibody fragment contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.
9. The method of claim 1 wherein the anti-IL-6 antibody or antibody fragment is a human, humanized, single chain or chimeric antibody.
10. The method of claim 1 wherein the anti-IL-6 antibody or antibody fragment comprises a VH polypeptide having at least 90% sequence identity to SEQ ID NO: 3, 18, 19, 656, or 657 and a VL polypeptide having at least 90% sequence identity to SEQ ID NO: 2, or 20.
11. The method of claim 1 wherein the anti-IL-6 antibody or antibody fragment is administered as part of a regimen that includes the administration of another therapeutic compound.
12. The method of claim 11 wherein the other therapeutic compound is selected from VEGF antagonists, EGFR antagonists, platins, taxols, irinotecan, 5-fluorouracil, gemcitabine, leucovorine, steroids, cyclophosphamide, melphalan, vinca alkaloids, mustines, tyrosine kinase inhibitors, radiotherapy, sex hormone antagonists, selective androgen receptor modulators, selective estrogen receptor modulators, PDGF antagonists, TNF antagonists, IL-1 antagonists, interleukins, IL-12R antagonists, Toxin conjugated monoclonal antibodies, tumor antigen specific monoclonal antibodies, Cetuximab, Bevacizumab, Pertuzumab, anti-CD20 antibodies, rituximab, ocrelizumab, ofatumumab, DXL625, Trastuzumab, or any combination thereof.
13. The method of claim 1 wherein the patient's coagulation profile is assessed by measurement of the patient's serum level of D-dimer.