Karel Van Damme, Dorine Sichien, Katrien Van der Borght, Justine Van Moorleghem, Sofie Van Gassen, Joseph Jorssen, Seppe De Winter, Elisabeth De Leeuw, Caihong Wang, Qingqing Chai, Anna Brotcke Zumsteg, Michael A. Schmid, Victor Bosteels, Pieter De Bleser, Manon Vanheerswynghels, Sofie De Prijck, Anna Bujko, Clint De Nolf, Martijn J. Schuijs, Bram Van Den Eeckhout, Ilse Rogiers, Robin Browaeys, Flore Thielemans, Katrien Quintelier, Jinke D’Hont, Tino Hochepied, Patricia Isnard Petit, Séverine Augier, Rachel Courtois, Stijn Verwaerde, Stijn Vanhee, Sjoerd Schetters, Charlotte L. Scott, Stein Aerts, Yvan Saeys, Alan J. Korman, Fabio Benigni, Davide Corti, Sophie Janssens, Niels Vandamme, António P. Baptista, Christophe Desmet, Dirk Elewaut, Hamida Hammad, Ariane Morel, Éric Vivier, Fabiane Sônego, Kader Thiam, Sofie Voet, Bianca Balbino, Bart N. Lambrecht
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 promotors, 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.