1. The anti-IgE mAb omalizumab induces adverse reactions by engaging Fcγ receptors
- Author
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Bianca Balbino, Julien Stackowicz, Kari C. Nadeau, Pauline Herviou, Ophélie Godon, Sébastien Brûlé, Delphine Sterlin, Andrew J. Murphy, Vera Voronina, Bruno Iannascoli, Odile Richard-Le Goff, Gaël A. Millot, Macdonald Lynn, Laurent L. Reber, Harris Faith, Pierre Bruhns, Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biophysique Moléculaire (Plate-forme), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Regeneron Pharmaceuticals [Tarrytown], Stanford University, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Commission (Marie Skłodowska-Curie Individual Fellowship H2020-MSCA-IF-2014 656086)European 235Research Council (ERC)–Seventh Framework Program (ERC-2013-CoG 616050)Institut Pasteur initiative for valorizing the applications of research (ValoExpress 2017)INSERM, ATIP-Avenir program'Investissement d’Avenir'(grant ANR-11-INBS-0006)Pasteur -Paris University (PPU) International Ph.DprogramFrench 'Fondation pour la Recherche Médicale FRMAP-HP, ANR-11-INBS-0006,FLI,France Life Imaging(2011), European Project: 616050,EC:FP7:ERC,ERC-2013-CoG,MYELOSHOCK(2014), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Allergy ,MESH: Asthma / immunology ,Omalizumab ,MESH: Anaphylaxis / immunology ,Immunoglobulin E ,MESH: Mice, Knockout ,Mice ,MESH: Asthma / pathology ,0302 clinical medicine ,Medicine ,MESH: Animals ,MESH: Drug Eruptions / pathology ,Mice, Knockout ,biology ,Concise Communication ,General Medicine ,MESH: Drug Eruptions / genetics ,3. Good health ,MESH: Anaphylaxis / pathology ,MESH: Omalizumab / genetics ,030220 oncology & carcinogenesis ,MESH: Drug Eruptions / immunology ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Drug Eruptions ,Antibody ,medicine.symptom ,Anaphylaxis ,medicine.drug ,MESH: Mutation ,MESH: Anaphylaxis / chemically induced ,medicine.drug_class ,Immunology ,Immunoglobulins ,Inflammation ,Monoclonal antibody ,MESH: Receptors, IgG / immunology ,03 medical and health sciences ,Immune system ,MESH: Omalizumab / adverse effects ,Animals ,MESH: Receptors, IgG / genetics ,MESH: Mice ,MESH: Omalizumab / pharmacology ,business.industry ,Receptors, IgG ,MESH: Asthma / drug therapy ,medicine.disease ,Asthma ,030104 developmental biology ,Mutation ,Mast cells ,MESH: Anaphylaxis / genetics ,biology.protein ,business - Abstract
International audience; Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of Omalizumab is associated with reported side effects, ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which Omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between Omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (FcγRs) in FcγR-humanized mice. We further developed an Fc-engineered mutant version of Omalizumab, and demonstrated that this mAb is equally potent as Omalizumab at blocking IgE-mediated allergic reactions, but does not induce FcγR-dependent adverse reactions. Overall, our data indicate that Omalizumab can induce skin inflammation and anaphylaxis by engaging FcγRs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.
- Published
- 2020
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