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 or hypercoagulation in patients having, or at risk of developing, diseases associated with abnormal blood coagulation or fibrinolysis and/or patients which are at increased risk or are being treated by a regimen that renders the patient at increased susceptibility to hypercoagulation or thrombosis such as patients who have previously had a stroke or heart attack or persons on a treatment regimen with a drug or chemotherapy and/or radiation that is associated with increased risk of thrombosis or hypercoagulation. 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.
1. A method of treating or reducing the risk of thrombosis in a patient at increased risk of developing thrombosis or hypercoagulation because of an underlying disease or treatment regimen potentially resulting in increased D-dimer levels, comprising administering to the patient a medicament comprising an anti-IL-6 antibody or anti-IL-6 antibody fragment in an amount effective to reduce D-dimer levels and thereby reduce the risk of said patient developing hypercoagulation or thrombosis, wherein the anti-IL-6 antibody or anti-IL-6 antibody fragment blocks the binding of human IL-6 to IL-6R1 and further blocks the binding of IL-6 to gp130, and further wherein said treatment method includes monitoring D-dimer levels before and/or after administration of the medicament to assess the patient's coagulation profile status.
2. The method of claim 1 , whereby method further comprises monitoring the patient to assess the coagulation profile after administration of the medicament.
3. The method of claim 1 , wherein the patient has had a stroke that renders the patient more susceptible to thrombosis or hypercoagulation.
4. The method of claim 1 , wherein the patient has an advanced cancer and/or is being treated with a drug that renders the patient more susceptible to thrombosis or hypercoagulation.
5. The method of claim 1 , wherein the patient has serum D-dimer levels which are at least 20% higher than normal prior to treatment.
6. The method of claim 1 , wherein the anti-IL-6 antibody or antibody fragment comprises the variable heavy chain of SEQ ID NO: 657 and the variable light chain of SEQ ID NO: 709 respectively or another antibody comprising variable heavy and/or light chain polypeptides comprising the same CDRs as the variable sequences of SEQ ID NOs:657 and 709.
7. The method of claim 6 , wherein the anti-IL-6 antibody or fragment comprises the heavy chain and light chain constant regions of SEQ ID NO:588 and SEQ ID NO:586, respectively.
8. The method of claim 1 , wherein the anti-IL-6 antibody or antibody fragment is aglycosylated and/or 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 said antibody comprises a human Fc derived from IgG1, IgG2, IgG3, or IgG4.
11. The method of claim 1 wherein said anti-IL-6 antibody or antibody fragment has an elimination half-life of at least about 22 days, at least about 25 days or at least about 30 days.
12. The method of claim 1 wherein said anti-IL-6 antibody or antibody fragment has a variable heavy sequence and a variable light sequence which are at least 98% identical -to the sequences of SEQ ID NOs: 19 and 20.
13. The method of claim 12 , wherein said anti-IL-6 antibody or antibody fragment comprises variable heavy and light sequences that are at least 95% identical to the sequences of SEQ ID NOs: 19 and 20.
14. The method claim 13 wherein said anti-IL-6 antibody or antibody fragment comprises the variable heavy and light sequences of SEQ ID NOs:19 and 20.
15. The method of claim 1 , wherein said anti-IL-6 antibody or fragment is comprised in a composition formulated for subcutaneous or intravenous injection.
16. The method of claim 1 , wherein said method further comprises the administration of at least one statin.
17. The method of claim 1 , wherein the patient has an elevated CRP level prior to administration of the IL-6 antibody or antibody fragment.
18. The method of claim 1 , wherein the patient is undergoing a therapeutic regimen comprising the administration of a chemotherapy agent or therapeutic compound which is one correlated with increased incidence of thrombosis or hypercoagulation.
19. The method of claim 1 , further comprising administration of one or more anti-coagulants.
20. The method of claim 19 , 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 a combination thereof.
21. The method of claim 1 , wherein the patient is one receiving transplanted cells, tissues or organs and an IL 6 antibody or antibody fragment is administered prior, concurrent or after transplant.
22. The method of claim 21 , wherein the patient has or is to receive a hematopoietic stem cell transplant (HCT), bone marrow transplantation (BMT).
23. The method of claim 21 , wherein the patient has or is to receive transplanted kidney, liver or lung tissues or organs.
24. The method of claim 21 , wherein the patient has or is to receive transplanted cells, tissues or organs potentially containing BDCAA4+ plasmacytoid dendritic cells.
25. The method of claim 21 , wherein the transplanted cells, tissues or organ comprise pancreatic, liver or skin cells.
26. The method of claim 25 , wherein the patient receiving the transplant has been treated with one or more rounds of chemotherapy or radiation.
27. The method of claim 25 , wherein an anti-IL-6 antibody or antibody fragment is administered within a week prior or after transplant.
28. The method of claim 25 , wherein an anti-IL-6 antibody or antibody fragment is administered within a day prior to or day after transplant.
29. The method of claim 21 , wherein the transplant subject receiving the transplant has leukemia or a lymphoma.
30. The method of claim 29 , wherein said leukemia is a chronic leukemia or an acute leukemia and the lymphoma is non-Hodgkin's lymphoma or Hodgkin's lymphoma.
31. The method of claim 29 , wherein said leukemia is chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), hairy cell leukemia, T cell prolymphcytic leukemia, (T-PLL) and large granular lymphocytic leukemia.