1. IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions
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Bianca Balbino, George Delidakis, Tae Hyun Kang, Makiko Watanabe, Kendra Triplett, Anja Lux, Navin Varadarajan, Odile Richard-Le Goff, Oana I. Lungu, Pierre Bruhns, George Georgiou, Corrine Alford, Gabrielle Romain, Margaret A. Lindorfer, Wissam Charab, Falk Nimmerjahn, Yan Jessie Zhang, Hidetaka Tanno, Wupeng Yan, Nicholas M. Marshall, Moses Donkor, Chang-Han Lee, Jiwon Lee, Ronald P. Taylor, Biliana Todorova, University of Texas at Austin [Austin], University of Houston, Anticorps en Thérapie et Pathologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Erlangen-Nürnberg [Germany], University of Virginia School of Medicine [US], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), University of Virginia, Department of Biochemistry and Molecular Genetics (xxx), University of Virginia [Charlottesville], We thank Y. Tanno for assistance with protein expression, A. Bui for assistance with liquid chromatography–tandem mass spectrometry, P. Tucker (University of Texas at Austin) for cancer cell lines, D. Lee (MD Anderson Cancer Center) for patient-derived primary acute lymphocytic leukemia cells, the Macromolecular Crystallography Facility of the University of Texas at Austin, the Berkeley Center for Structural Biology, the Advanced Light Source (supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under contract DE-AC02-05CH11231), the Proteomics Facility at the University of Texas at Austin (supported by grant RP110782 from the Cancer Prevention Research Training Program), and A. Nicola and the Plate-Forme d'Imagerie Dynamique (Institut Pasteur, Paris) for help with the bioluminescence experiments. Supported by the Clayton Foundation, the Institut Pasteur (P.B. laboratory), the Institut National de la Santé et de la Recherche Médicale (P.B. laboratory), the European Research Council Seventh Frame-work Program (ERC-2013-CoG 616050 for the P.B. laboratory), the Pasteur–Paris University International PhD program (B.B.), the Cancer Prevention Research Training Program (RP140108 to M.D., RP160015 to H.T., and RP130570 to N.V.), the American Cancer Society (123506-PF-13-354-01-CDD to N.M.), Uehara Memorial Foundation (H.T.), Japan Society for the Promotion of Science (H.T.), Deutsche Forschungsgemeinschaft (CRC1181-A07 to F.N.), the US National Institutes of Health (R01CA174385 to N.V., and R01 GM104896 to Y.J.Z.) and the Welch Foundation (F-1778 to Y.J.Z.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Cancer Prevention and Research Institute of Texas., European Project: 616050,EC:FP7:ERC,ERC-2013-CoG,MYELOSHOCK(2014), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Virginia, Martin, Marie, and Role of myeloid cells, their mediators and their antibody receptors in allergic shock (anaphylaxis) using humanized mouse models and clinical samples - MYELOSHOCK - - EC:FP7:ERC2014-09-01 - 2019-08-31 - 616050 - VALID
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Cytotoxicity, Immunologic ,0301 basic medicine ,Cellular immunity ,MESH: Complement C1q ,MESH: Immunotherapy ,Crystallography, X-Ray ,Mass Spectrometry ,MESH: Antibodies, Monoclonal ,Mice ,Tandem Mass Spectrometry ,Neoplasms ,Immunology and Allergy ,MESH: Animals ,MESH: Neoplasms ,Cytotoxicity ,Receptor ,MESH: Phagocytosis ,MESH: Crystallization ,MESH: Immunoglobulin G ,biology ,Effector ,Antibodies, Monoclonal ,MESH: Enzyme-Linked Immunosorbent Assay ,MESH: Chromatography, Gel ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Burkitt Lymphoma ,3. Good health ,Cell biology ,MESH: Surface Plasmon Resonance ,Chromatography, Gel ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Immunotherapy ,Lymphoma, Large B-Cell, Diffuse ,Antibody ,Crystallization ,Lymphoma, B-Cell ,MESH: Cell Line, Tumor ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Immunology ,Enzyme-Linked Immunosorbent Assay ,In Vitro Techniques ,MESH: Receptors, IgG ,MESH: Immunoglobulin Fc Fragments ,03 medical and health sciences ,Classical complement pathway ,Immune system ,Phagocytosis ,Cell Line, Tumor ,Animals ,Humans ,MESH: Cytotoxicity, Immunologic ,MESH: Mice ,MESH: Lymphoma, B-Cell ,MESH: In Vitro Techniques ,MESH: Mass Spectrometry ,MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma ,MESH: Humans ,Complement C1q ,Receptors, IgG ,MESH: Tandem Mass Spectrometry ,Surface Plasmon Resonance ,MESH: Crystallography, X-Ray ,Immunoglobulin Fc Fragments ,Complement system ,MESH: Burkitt Lymphoma ,030104 developmental biology ,Immunoglobulin G ,biology.protein ,MESH: Lymphoma, Large B-Cell, Diffuse ,MESH: Chromatography, Liquid ,Chromatography, Liquid - Abstract
International audience; Engineered crystallizable fragment (Fc) regions of antibody domains, which assume a unique and unprecedented asymmetric structure within the homodimeric Fc polypeptide, enable completely selective binding to the complement component C1q and activation of complement via the classical pathway without any concomitant engagement of the Fcγ receptor (FcγR). We used the engineered Fc domains to demonstrate in vitro and in mouse models that for therapeutic antibodies, complement-dependent cell-mediated cytotoxicity (CDCC) and complement-dependent cell-mediated phagocytosis (CDCP) by immunological effector molecules mediated the clearance of target cells with kinetics and efficacy comparable to those of the FcγR-dependent effector functions that are much better studied, while they circumvented certain adverse reactions associated with FcγR engagement. Collectively, our data highlight the importance of CDCC and CDCP in monoclonal-antibody function and provide an experimental approach for delineating the effect of complement-dependent effector-cell engagement in various therapeutic settings.
- Published
- 2017
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