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Combination of Transmembrane Activator and Calcium Modulator (19) TZZ ¥¥__T (11) EP 2 233 149 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 38/17 (2006.01) A61K 39/395 (2006.01) 10.02.2016 Bulletin 2016/06 C07K 19/00 (2006.01) C07K 16/28 (2006.01) A61P 37/00 (2006.01) (21) Application number: 10167232.7 (22) Date of filing: 16.10.2008 (54) Combination of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and anti-CD20 agents for treatment of autoimmune disease Kombination von Transmembran-Aktivator und Calcium-Modulator und Cyclophilin Ligand Interaktor (TACI) und anti-CD20 Mitteln zur Behandlung von Autoimmunerkrankungen Combinaison de l’activateur transmembranaire et modulateur calcique et interacteur du ligand de cyclophiline (TACI) et d’un agent anti-CD20 pour le traitement des maladies auto-immunes (84) Designated Contracting States: (74) Representative: Griffin, Philippa Jane AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Mathys & Squire LLP HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT The Shard RO SE SI SK TR 32 London Bridge Street Designated Extension States: London SE1 9SG (GB) AL BA MK RS (56) References cited: (30) Priority: 16.10.2007 US 980331 P WO-A-2005/005462 WO-A-2006/068867 WO-A2-2007/134326 (43) Date of publication of application: 29.09.2010 Bulletin 2010/39 • SILVERMAN G J ET AL: "B cell modulation in rheumatology" CURRENT OPINION IN (62) Document number(s) of the earlier application(s) in PHARMACOLOGY - CANCER/ accordance with Art. 76 EPC: IMMUNOMODULATION 200708 GB, vol. 7, no. 4, 08838758.4 / 2 200 631 August 2007 (2007-08), pages 426-433, XP002515031 ISSN: 1471-4892 (73) Proprietors: • CHAN A ET AL: "Rescue therapy with anti-CD20 • ZymoGenetics, Inc. treatment in neuroimmunologic breakthrough Seattle, Washington 98102 (US) disease [5]" JOURNAL OF NEUROLOGY 200711 • ARES TRADING S.A. DE, vol. 254, no. 11, November 2007 (2007-11), 1170 Aubonne (CH) pages 1604-1606, XP002515032 • STUVE O ET AL: "Clinical stabilization and (72) Inventors: effective B-lymphocyte depletion in the • Broly, Herve cerebrospinal fluid and peripheral blood of a F-33650 Saint Selve (FR) patient with fulminant relapsing-remitting • Ponce Jr., Rafael A. multiple sclerosis" ARCHIVES OF NEUROLOGY Seattle, WA 98103 (US) 200510US, vol. 62, no. 10, October 2005 (2005-10), • Graffner, Hans Otto Lennart pages 1620-1623, XP002515033 252 84 Helsingborg (SE) • Peano, Sergio I-10015 Ivrea (to) (IT) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 233 149 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 233 149 B1 • ANOLIK ET AL: "New treatments for SLE: cell- • DILILLO DAVID J ET AL: "Maintenance of long- depleting and anti-cytokine therapies" lived plasma cells and serological memory BAILLIERE’S BEST PRACTICE AND RESEARCH. despite mature and memory B cell depletion CLINICAL REUMATOLOGY, BAILLIERE during CD20 immunotherapy in mice." JOURNAL TINDALL, LONDON, GB, vol. 19, no. 5, 1 October OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 1 2005 (2005-10-01), pages 859-878, XP005140891 JAN 2008, vol. 180, no. 1, 1 January 2008 ISSN: 1521-6942 (2008-01-01), pages 361-371, XP002515037 ISSN: • MUNAFO A ET AL: "Safety, pharmacokinetics 0022-1767 and pharmacodynamics of atacicept in healthy • PONCE RAFAEL: "Preclinical support for volunteers" EUROPEAN JOURNAL OF CLINICAL combination therapy in the treatment of PHARMACOLOGY 200707 DE, vol. 63, no. 7, July autoimmunity with atacicept." TOXICOLOGIC 2007 (2007-07), pages 647-656, XP002515034 PATHOLOGY 2009 LNKD- PUBMED:19171929, ISSN: 0031-6970 vol. 37, no. 1, 2009, pages 89-99, XP002593220 • DATABASE BIOSIS [Online] BIOSCIENCES ISSN: 1533-1601 INFORMATION SERVICE, PHILADELPHIA, PA, US; September 2008 (2008-09), CARBONATTO MICHELA ET AL: "Nonclinical safety, pharmacokinetics, and pharmacodynamics of atacicept" XP002515379 Database accession no. PREV200800586339 & TOXICOLOGICAL SCIENCES, vol. 105, no. 1, September 2008 (2008-09), pages 200-210, ISSN: 1096-6080 • "InNexus Lead Candidate DXL625 Outperforms Rituxan in Additional Animal Studies" INTERNET CITATION, [Online] 2008, pages 1-2, XP002515036 INTERNET Retrieved from the Internet: URL:http: //www.scientificblogging.com/prin t/32525> & INNEXUS BIOTECHNOLOGY, INC: "Presentation American Association for Cancer Research, San Diego, California" , 2008, pages 1-14, Retrieved from the Internet: URL:http: //www.innexusbiotech.com/docs/AAC R2008SLIDES.pdf> 2 EP 2 233 149 B1 Description FIELD OF THE INVENTION 5 [0001] The invention relates to novel combination therapies involving BLyS or BLyS/APRIL inhibition using a TACi- Fc-fusion protein and anti-CD 20 agent for the treatment of autoimmune diseases, as defined in the claims. BACKGROUND OF THE INVENTION 10 [0002] Lymphocytes are one of several populations of white blood cells; they specifically recognize and respond to foreign antigen. The three major classes of lymphocytes are B lymphocytes (B cells), T lymphocytes (T cells) and natural killer (NK) cells. B lymphocytes are the cells responsible for antibody production and provide humoral immunity. B cells mature within the bone marrow and leave the marrow expressing an antigen-binding antibody on their cell surface: When a naive B cell first encounters the antigen for which its membrane-bound antibody is specific, the cell begins to divide 15 rapidly and its progeny differentiate into memory B cells and effector cells called plasma cells. Memory B cells have a longer life span and continue to express membrane-bound antibody with the same specificity as the original parent cell. Plasma cells do not produce membrane bound antibody but instead produce secreted form of the antibody. Secreted antibodies are the major effector molecules of humoral immunity. [0003] A group of tumor necrosis factor (TNF) receptors found on the surface of B cells under various conditions are 20 among the cellular regulators of B cell function in the immune system. In particular, three TNF receptors: transmembrane activatorand CAMLinteractor (TACI), Bcell activatorbelonging to theTNF family receptor(BAFF-R), and B cell maturation protein (BCMA) are known to bind one or both TNF ligands - B Lymphocyte stimulator (BLyS also known as BAFF, TALL-1, ztnf4 and THANK) and a proliferation-inducing ligand (APRIL). Specifically, TACI and BCMA are known to bind both BLyS and APRIL and BAFF-R binds only BLyS. 25 [0004] A number of BLyS antagonists have been developed in order to block the various functions of BLyS, which include but should not be limited to B cell co-stimulation, plasmablast and plasma cell survival, Ig class switching, enhanced B-cell antigen presenting cell function, survival of malignant B cells, development of B-1 cell function, B cell development beyond the T-1 stage, and complete germinal centre formation Some of these molecules can also bind to and block the effect of APRIL on B cells and other components of the immune system (Dillon et al. (2006) Nat. Rev. 30 Drug Dis. 5, 235-246). Molecules that have been developed to affect B cell function by interfering with BLyS and/or APRIL binding include BLyS antibodies such as Lymphostat-B (Belimumab) (Baker et al, (2003) Arthritis Rheum, 48, 3253-3265 and WO 02/02641); receptor-extracellular domain/Fc domain fusions proteins such as TACI-Ig, including one particular embodiment, atacicept (U.S. Patent Application No. 20060034852), BAFF-R-Fc (WO 05/0000351), and BCMA-Ig or other fusion proteins utilizing receptor extracellular domains. A further class of BLyS antagonists include 35 other molecules relying on BLyS binding ability to block binding to its receptors such as AMG 623, receptor antibodies, and other molecules disclosed in WO 03/035846 and WO 02/16312. [0005] The CD20 antigen (also called human B-lymphocyte-restricted differentiation antigen, Bp35) is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes (Valentine et al. J. Biol. Chent. 264 (19): 11282-11287 (1989) ; and Einfeld et al. EMBO J. 7 (3): 711-717 (1988)). The 40 antigen is also expressed on greater than 90% of B cell non-Hodgkin’s lymphomas (NHL) (Anderson et al. Blood 63 (6): 1424-1433 (1984)), but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissues (Tedder et al. J. Immunol. 135 (2): 973-979 (1985)). CD20 regulates an early step (s) in the activation process for cell cycle initiation and differentiation (Tedder et al., supra) and possibly functions as a calcium ion channel (Tedder et al. J. Cell. Biochem. 14D: 195 (1990)). 45 [0006] Given the expression of CD20 on B cells, this antigen can serve as a candidate for "targeting" of those cells to treat autoimmune diseases. In essence, such targeting can be generalized as follows: antibodies specific to the CD20 surface antigen of B cells are administered to a patient. These anti-CD20 antibodies specifically bind to the CD20 antigen of (ostensibly) both B cells producing normal antibodies and detrimental autoantibodies; the antibody bound to the CD20 surface antigen may lead to the destruction and depletion of these B cells. Irrespective of the approach, a primary goal 50 is to destroy the cells producing the autoantibodies; the specific approach can be determined by the particular anti-CD20 antibody which is utilized and, thus, the available approaches to targeting the CD20 antigen can vary considerably. [0007] The rituximab (RITUXAN®) antibody is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen.
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