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Ep 2505209 A1 (19) TZZ Z Z_T (11) EP 2 505 209 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 03.10.2012 Bulletin 2012/40 A61K 39/395 (2006.01) C07K 16/00 (2006.01) A61P 35/00 (2006.01) C07K 16/28 (2006.01) (21) Application number: 12155325.9 (22) Date of filing: 26.06.2007 (84) Designated Contracting States: • Johnson, Leslie AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Darnestown, MD 20874 (US) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • Huang, Ling SI SK TR Bethesda, MD 20817 (US) (30) Priority: 26.06.2006 US 816688 P (74) Representative: Vossius & Partner Siebertstrasse 4 (62) Document number(s) of the earlier application(s) in 81675 München (DE) accordance with Art. 76 EPC: 07812341.1 / 2 029 173 Remarks: This application was filed on 14-02-2012 as a (71) Applicant: MacroGenics, Inc. divisional application to the application mentioned Rockville, MD 20850 (US) under INID code 62. (72) Inventors: • Gerena, Robyn Sandston, VA 23510 (US) (54) Fcgamma-RIIB-specific antibodies and methods of the use thereof (57) The present invention relates to antibodies or ma, an autoimmune disorder, an inflammatory disorder, fragments thereof that specifically bind FcγRIIB, partic- an IgE-mediated allergic disorder, or one or more symp- ularly human FcγRIIB, with greater affinity than said an- toms thereof. The invention provides methods of enhanc- tibodies or fragments thereof bind FcγRIIA, particularly ing the therapeutic effect of therapeutic antibodies by human FcγRIIA. The present invention also provides the administering the antibodies of the invention to enhance use of an anti-FcγRIIB antibody or an antigen-binding the effector function of the therapeutic antibodies. The fragment thereof, as a single agent therapy for the treat- invention also provides methods of enhancing efficacy ment, prevention, management, or amelioration of a can- of a vaccine composition by administering the antibodies cer, preferably a B-cell malignancy, particularly, B-cell of the invention. chronic lymphocytic leukemia or non-Hodgkin’s lympho- EP 2 505 209 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 505 209 A1 Description CROSS-REFERENCE TO RELATED APPLICATIONS 5 [0001] This application claims benefit of U.S. Provisional Patent Application Serial No.: 60/816,688, filed June 26, 2006, the contents of which are incorporated herein by reference for all purposes. 1. FIELD OF THE INVENTION 10 [0002] The present invention relates to antibodies or fragments thereof that specifically bind FcγRIIB, particularly human FcγRIIB, with greater affinity than said antibodies or fragments thereof bind FcγRIIA, particularly human FcγRIIA. The present invention also encompasses the use of an anti-FcγRIIB antibody or an antigen-binding fragment thereof, as a single agent therapy for the treatment, prevention, management, or amelioration of a cancer, preferably a B-cell malignancy, particularly, B-cell chronic lymphocytic leukemia or non-Hodgkin’s lymphoma, an autoimmune disorder, an 15 inflammatory disorder, an IgE-mediated allergic disorder, or one or more symptoms thereof. The present invention also encompasses the use of an anti-FcγRIIB antibody or an antigen-binding fragment thereof, in combination with other cancer therapies. The present invention provides pharmaceutical compositions comprising an anti-FcγRIIB antibody or an antigen-binding fragment thereof, in amounts effective to prevent, treat, manage, or ameliorate a cancer, such as a B-cell malignancy, an autoimmune disorder, an inflammatory disorder, an IgE-mediated allergic disorder, or one or more 20 symptoms thereof. The invention further provides methods of enhancing the therapeutic effect of therapeutic antibodies by administering the antibodies of the invention to enhance the effector function of the therapeutic antibodies. The invention also provides methods of enhancing efficacy of a vaccine composition by administering the antibodies of the invention with a vaccine composition. 25 2. BACKGROUND OF THE INVENTION 2.1 Fc RECEPTORS AND THEIR ROLES IN THE IMMUNE SYSTEM [0003] The interaction of antibody-antigen complexes with cells of the immune system results in a wide array of 30 responses, ranging from effector functions such as antibody-dependent cell-mediated cytotoxicity, mast cell degranu- lation, and phagocytosis to immunomodulatory signals such as regulating lymphocyte proliferation and antibody secre- tion. All these interactions are initiated through the binding of the Fc domain of antibodies or immune complexes to specialized cell surface receptors on hematopoietic cells. The diversity of cellular responses triggered by antibodies and immune complexes results from the structural heterogeneity of Fc receptors. Fc receptors share structurally related 35 ligand binding domains which presumably mediate intracellular signaling. [0004] The Fc receptors, members of the immunoglobulin gene superfamily of proteins, are surface glycoproteins that can bind the Fc portion of immunoglobulin molecules. Each member of the family recognizes immunoglobulins of one or more isotypes through a recognition domain on the a chain of the Fc receptor. Fc receptors are defined by their specificity for immunoglobulin subtypes. Fc receptors for IgG are referred to as FcγR, for IgE as FcεR, and for IgA as 40 FcαR. Different accessory cells bear Fc receptors for antibodies of different isotype, and the isotype of the antibody determines which accessory cells will be engaged in a given response (reviewed by Ravetch J.V. et al. 1991, Annu. Rev. Immunol. 9: 457-92; Gerber J.S. et al. 2001 Microbes and Infection, 3: 131-139; Billadeau D.D. et al, 2002, The Journal of Clinical investigation, 2(109): 161-1681; Ravetch J.V. et al. 2000, Science, 290: 84-89; Ravetch J.V. et al., 2001 Annu. Rev. Immunol. 19:275-90; Ravetch J.V. 1994, Cell, 78(4): 553-60). The different Fc receptors, the cells that 45 express them, and their isotype specificity is summarized in Table 1 (adapted from Immunobiology: The Immune System in Health and Disease, 4th ed. 1999, Elsevier Science Ltd/Garland Publishing, New York). Fcy Receptors 50 [0005] Each member of this family is an integral membrane glycoprotein, possessing extracellular domains related to a C2-set of immunoglobulin-related domains, a single membrane spanning domain and an intracytoplasmic domain of variable length. There are three known FcγRs, designated FcγRI(CD64), FcγRII(CD32), and FcγRIII(CD16). The three receptors are encoded by distinct genes; however, the extensive homology between the three family members suggest they arose from a common progenitor perhaps by gene duplication. This invention specifically focuses on FcγRII(CD32). 55 FcγRII(CD32) [0006] FcγRII proteins are 40 KDa integral membrane glycoproteins which bind only the complexed IgG due to a low 2 EP 2 505 209 A1 affinity for monomeric Ig (106 M-1). This receptor is the most widely expressed FcγR, present on all hematopoietic cells, including monocytes, macrophages, B cells, NK cells, neutrophils, mast cells, and platelets. FcγRII has only two immu- noglobulin-like regions in its immunoglobulin binding chain and hence a much lower affinity for IgG than FcγRI. There are three human FcγRII genes (FcγRII-A, FcγRII-B, FcγRII-C), all of which bind IgG in aggregates or immune complexes. 5 [0007] Distinct differences within the cytoplasmic domains of FcγRII-A (CD32A) and FcγRII-B (CD32B) create two functionally heterogeneous responses to receptor ligation. The fundamental difference is that the A isoform initiates intracellular signaling leading to cell activation such as phagocytosis and respiratory burst, whereas the B isoform initiates inhibitory signals, e.g., inhibiting B-cell activation. 10 Signaling through FcγRs [0008] Both activating and inhibitory signals are transduced through the FcγRs following ligation. These diametrically opposing functions result from structural differences among the different receptor isoform. Two distinct domains within the cytoplasmic signaling domains of the receptor called immunoreceptor tyrosine based activation motifs (ITAMs) or 15 immunoreceptor tyrosine based inhibitory motifs (ITIMS) account for the different responses. The recruitment of different cytoplasmic enzymes to these structures dictates the outcome of the FcγR-mediated cellular responses. ITAM-containing FcγR complexes include FcγRI, FcγRIIA, FcγRIIIA, whereas ITIM-containing complexes only include FcγRIIB. [0009] Human neutrophils express the FcγRIIA gene. FcγRIIA clustering via immune complexes or specific antibody cross-linking serves to aggregate ITAMs along with receptor-associated kinases which facilitate ITAM phosphorylation. 20 ITAM phosphorylation serves as a docking site for Syk kinase, activation of which results in activation of downstream substrates (e.g., PI3K). Cellular activation leads to release of proinflammatory mediators. [0010] The FcγRIIB gene is expressed on B lymphocytes; its extracellular domain is 96% identical to FcγRIIA and binds IgG complexes in an indistinguishable manner. The presence of an ITIM in the cytoplasmic domain of FcγRIIB defines this inhibitory subclass of FcγR. Recently the molecular basis of this inhibition was established. When colligated 25 along with an activating FcγR, the ITIM in FcγRIIB becomes phosphorylated and attracts the SH2 domain of the inositol polyphosphate 5’-phosphatase, (SHIP), which hydrolyzes phosphoinositol messengers released as a consequence of ITAM-containing FcγR- mediated tyrosine kinase activation, consequently preventing the influx of intracellular
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