Animals; Histocompatibility Antigens Class I; Humans; Immunoglobulin G; Macaca; Mice; Receptors, Fc; Receptors, IgG; Species Specificity; Immunology and Allergy; Immunology
Abstract :
[en] Fc receptors mediate antibody effector functions. Immunoglobulin G (IgG), the predominant antibody in circulation and in clinical use, engages diverse Fc gamma (Fcγ) receptors differentially expressed across cell types. Here, we provide a comprehensive overview of Fcγ receptor and neonatal Fc receptor (FcRn) expression in humans, macaques, and mice. This analysis revealed substantial differences in Fcγ receptor diversity, cell-specific expression, and regulatory mechanisms that compromise the translation of mouse and macaque models for antibody research. To improve preclinical modeling, we generated a mouse in which humanized Fcγ receptors (FcγRI/CD64, FcγRIIA/CD32A, FcγRIIB/CD32B, FcγRIIIA/CD16A, and FcγRIIIB/CD16B), expressed under control of human promo-tors, replace their murine counterparts. This model also incorporates human FcRn to improve antibody pharmacokinetics. Humanization resulted in more faithful Fcγ receptor expression. We validated receptor functionality and demonstrated how cytokines modulate their expression. Together, this cross-species Fcγ receptor atlas and humanized mouse model can improve the preclinical evaluation of antibody-based therapeutics.
Disciplines :
Hematology Immunology & infectious disease
Author, co-author :
Van Damme, Karel F. A. ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Sichien, Dorine; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; argenx, Ghent, Belgium
Van der Borght, Katrien ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; VIB Flow Core, VIB Center for Inflammation Research, Ghent, Belgium ; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
Van Moorleghem, Justine ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Van Gassen, Sofie ; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium ; Data Mining and Modeling for Biomedicine Group, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium
Jorssen, Joseph ; Université de Liège - ULiège > GIGA > GIGA Immunobiology - Cellular and Molecular Immunology
De Winter, Seppe ; VIB Center for Brain & Disease Research, Leuven, Belgium ; Department of Human Genetics, KU Leuven, Leuven, Belgium
De Leeuw, Elisabeth ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Wang, Caihong ; Vir Biotechnology, San Francisco, United States ; Bellinzona, Switzerland
Chai, Qingqing ; Vir Biotechnology, San Francisco, United States ; Bellinzona, Switzerland
Zumsteg, Anna Brotcke; Vir Biotechnology, San Francisco, United States ; Bellinzona, Switzerland
Schmid, Michael A. ; Vir Biotechnology, San Francisco, United States ; Bellinzona, Switzerland
Bosteels, Victor ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Laboratory for ER Stress and Inflammation, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium
De Bleser, Pieter ; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium ; Data Mining and Modeling for Biomedicine Group, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium
Vanheerswynghels, Manon ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
De Prijck, Sofie ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Bujko, Anna ; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium ; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Tribune Therapeutics, Oslo, Norway
De Nolf, Clint ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Laboratory for ER Stress and Inflammation, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Barriers in Inflammation, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium
Schuijs, Martijn J. ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
Van Den Eeckhout, Bram; argenx, Ghent, Belgium
Rogiers, Ilse; argenx, Ghent, Belgium
Browaeys, Robin ; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium ; Bioinformatics Expertise Unit, VIB Center for Inflammation Research, Ghent, Belgium
Thielemans, Flore; argenx, Ghent, Belgium
Quintelier, Katrien ; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium ; Data Mining and Modeling for Biomedicine Group, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
D’hont, Jinke ; Transgenic Core Facility, VIB Center for Inflammation Research, Ghent, Belgium ; Transgenic Core Facility, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
Hochepied, Tino ; Transgenic Core Facility, VIB Center for Inflammation Research, Ghent, Belgium ; Transgenic Core Facility, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
Petit, Patricia Isnard; genOway, Lyon, France
Augier, Séverine ; Innate Pharma, Marseille, France
Courtois, Rachel ; Innate Pharma, Marseille, France
Verwaerde, Stijn ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Vanhee, Stijn ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Department of Head and Skin, Faculty of Medicine and Health, Ghent University, Ghent, Belgium
Schetters, Sjoerd ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Scott, Charlotte L. ; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium ; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium
Aerts, Stein ; VIB Center for Brain & Disease Research, Leuven, Belgium ; Department of Human Genetics, KU Leuven, Leuven, Belgium
Saeys, Yvan ; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium ; Data Mining and Modeling for Biomedicine Group, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium
Korman, Alan J. ; Vir Biotechnology, San Francisco, United States ; Blue-sphere Bio, Pittsburgh, United States
Benigni, Fabio ; Vir Biotechnology, San Francisco, United States
Corti, Davide ; Vir Biotechnology, San Francisco, United States
Janssens, Sophie ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Laboratory for ER Stress and Inflammation, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium
Vandamme, Niels ; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium ; VIB Single Cell Core, Belgium
Baptista, Antonio P. ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Desmet, Christophe ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF)
Elewaut, Dirk; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Molecular Immunology and Inflammation Unit, VIB Center for Inflammation Research, Ghent University, Ghent, Belgium
Hammad, Hamida; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Morel, Ariane ; Innate Pharma, Marseille, France
Vivier, Eric ; Innate Pharma, Marseille, France ; Aix Marseille Université, Centre National de la Recherche Scientifique, INSERM, Centre d’Immunologie de Marseille-luminy, Marseille, France ; Assis-tance Publique-hôpitaux de Marseille, Hôpital de la Timone, Marseille Immunopôle, Marseille, France
Sônego, Fabiane ; genOway, Lyon, France
Thiam, Kader ; genOway, Lyon, France
Voet, Sofie; argenx, Ghent, Belgium
Balbino, Bianca; argenx, Ghent, Belgium
Lambrecht, Bart N. ; Laboratory of Mucosal Immunology, VIB-ugent Center for Inflammation Research, Ghent University, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands ; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
IWT - Agentschap Innoveren en Ondernemen ERC - European Research Council FWO - Fonds Wetenschappelijk Onderzoek Vlaanderen
Funding text :
This research was supported by a VLAIO research grant BC.2020.3084 (B.N.L., argenx); ERC Consolidator grant DCRIDDLE-819314 (S.J.); and Research Foundation-Flanders, Belgium (FWO) grant 1244321N and FWO grant G0A7422N (S. Vanhee).
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