(19) TZZ ¥_ _T (11) EP 2 376 126 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 39/00 (2006.01) C07K 16/24 (2006.01) 20.12.2017 Bulletin 2017/51 (86) International application number: (21) Application number: 09830695.4 PCT/US2009/006266 (22) Date of filing: 24.11.2009 (87) International publication number: WO 2010/065077 (10.06.2010 Gazette 2010/23) (54) ANTAGONISTS OF IL-6 TO PREVENT OR TREAT THROMBOSIS ANTAGONISTEN VON IL-6 ZUR PRÄVENTION ODER BEHANDLUNG VON THROMBOSE ANTAGONISTES D IL-6 POUR PRÉVENIR OU TRAITER LA THROMBOSE (84) Designated Contracting States: • MATSUYAMA MASASHI ET AL: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR "Anti-interleukin-6 receptor antibody HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL (tocilizumab) treatment of multicentric PT RO SE SI SK SM TR Castleman’s disease", INTERNAL MEDICINE, JAPANESE SOCIETY OF INTERNAL MEDICINE, (30) Priority: 05.02.2009 US 366567 TOKYO, JP; BIOSCIENCES INFORMATION 14.07.2009 US 502581 SERVICE, PHILADELPHIA, PA, US, vol. 46, 1 25.11.2008 US 117811 P January 2007 (2007-01-01), pages 771-774, 25.11.2008 US 117861 P XP002696891, ISSN: 0918-2918, DOI: 24.02.2009 US 391717 10.2169/INTERNALMEDICINE.46.6262 06.03.2009 US 399156 • EMILLE D ET AL: "ADMINISTRATION OF AN 25.11.2008 US 117839 P ANTI-INTERLEUKIN-6 MONOCLONAL 24.02.2009 US 391615 ANTIBODY TO PATIENTS WITH ACQUIRED IMUNODEFICIENCY SYNDROME AND (43) Date of publication of application: LYMPHOMA: EFFECT ON LYMPHOMA GROWTH 19.10.2011 Bulletin 2011/42 AND ON B CLINICAL SYMPTOMS", BLOOD, AMERICAN SOCIETY OFHEMATOLOGY, US, vol. (73) Proprietor: AlderBio Holdings LLC 84, no. 8, 15 October 1994 (1994-10-15), pages Las Vegas, NV 89109 (US) 2472-2479, XP001088120, ISSN: 0006-4971 • M. H. ZAKI ET AL: "Proc Am Soc Clin Oncol", 2003 (72) Inventor: SMITH, Jeffrey, T.L. ASCO ANNUAL MEETING - DEVELOPMENTAL Bellevue THERAPEUTICS - CLINICAL PHARMACOLOGY WA 98004 (US) AND IMMUNOTHERAPY , vol. 22, 697, 2003, XP055045899, Retrieved from the Internet: (74) Representative: Boult Wade Tennant URL:http://www.asco.org/ASCOv2/Meetings/Ab Verulam Gardens stracts?&vmview=abst_detail_view&confID=23 70 Gray’s Inn Road &abstractID=100701 [retrieved on 2012-11-27] London WC1X 8BT (GB) • BATAILLE R ET AL: "Biologic effects of anti-interleukin-6 murine monoclonal antibody in (56) References cited: advanced multiple myeloma", BLOOD, WO-A1-2004/039826 WO-A2-2008/065378 AMERICAN SOCIETY OFHEMATOLOGY, US, vol. 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In particular, this invention pertains to an anti-IL-6 antibody comprising a VL polypeptide of SEQ ID NO:709 and a light chain constant 10 region of SEQ ID NO: 586; and a VH polypeptide of SEQ ID NO:657 and a heavy chain constant region of SEQ ID NO: 588 for use in a method of treating a patient having an advanced cancer associated with hypercoagulation, wherein the anti-IL-6 antibody is aglycosylated. [0002] In another embodiment the invention provides novel combination therapies wherein the anti-IL-6 antibody of the invention is administered in combination with at least one other therapeutic compound e.g., a statin,including but 15 not limited to atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simv- astatin, or any combination thereof; a chemotherapeutic agent such as VEGF antagonists, EGFR antagonists, platins, taxols, irinotecan, 5-fluorouracil, gemcitabine, leucovorin, steroids, cyclophosphamide, melphalan, vinca alkaloids (e.g., vinblastine, vincristine, vindesine and vinorelbine), mustines, tyrosine kinase inhibitors, radiotherapy, sex hormone an- tagonists, selective androgen receptor modulators, selective estrogen receptor modulators, PDGF antagonists, TNF 20 antagonists, IL-1 antagonists, interleukins (e.g. IL-12 or IL-2), IL-12R antagonists, toxin conjugated monoclonal antibod- ies, tumor antigen specific monoclonal antibodies, Erbitux™ , Avastin™, Pertuzumab, anti-CD20 antibodies, RituxanTM, ocrelizumab, ofatumumab, DXL625, Herceptin.™, or any combination thereof; or an an anti-coagulant such as abciximab (ReoPro™), acenocoumarol, antithrombin, argatroban, aspirin, bivalirudin (Angiomax™), clopidogrel, dabigatran, da- bigatran, etexilate, (Pradaxa™/Pradax™), desirudin (Revasc™/Iprivask™), dipyridamole, eptifibatide (Integrilin™), fon- 25 daparinux, heparin, hirudin, idraparinux, lepirudin (Refludan™), low molecular weight heparin, Melagatran, phenindione, phenprocoumon, ticlopidine, tirofiban (Aggrastat™), warfarin, ximelagatran, ximelagatran (Exanta™/ Exarta™), or any combination thereof. Description of Related Art 30 [0003] Thrombosis is a significant cause of mortality in cancer patients. Bick, N Engl J Med 349:109-111 (2003). For example, serious, life-threatening thrombotic events occur in approximately 6% of lung cancer patients. Alguire et al., J Clin Oncol 2004 Vol 22 (July 15th Supplement) No. 14S: 8082. Cancer patients often exhibit hypercoagulation, in which the coagulation system has an increased clotting tendency. Rickles and Edwards, Blood 62:14-31 (1983).