Cross-species cellular mapping and humanization of Fcγ receptors to advance antibody modeling

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.