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

ABSTRACT: Fc receptors mediate the effector functions of therapeutic antibodies. Immunoglobulin G (IgG), the predominant antibody in circulation and clinical use, engages diverse Fc gamma (Fcγ) receptors that are expressed by multiple immune and structural cells. Here, we provide a comprehensive overview of Fcγ receptors and FcRn expression at both the transcriptomic and proteomic level in humans, macaques, and mice. We reveal species-specific differences in both Fcγ receptor diversity and cell-specific expression profile that compromise the translation of mouse and macaque preclinical models for antibody research. To overcome this, we generated a new mouse model in which human FcγRI (hCD64), FcγRIIA (hCD32A), FcγRIIB (hCD32B), FcγRIIIA (hCD16A), FcγRIIIB (hCD16B) is expressed under control of the relevant human promotors, replacing the murine counterparts (FcγRI, FcγRIIB, FcγRIII, and FcγRIV). Furthermore, to improve human antibody pharmacokinetics, murine FcRn was replaced by its human analog. We comprehensively mapped the expression of the knock-in receptors, and found that humanization led to much more faithful cell-specific Fcg receptor expression. We validated the functionality of these knock-in human receptors through in vitro and in vivo antibody-dependent cellular cytotoxicity, anaphylaxis and antigen presentation assays. This cross-species Fcγ receptor atlas and humanized mouse model with refined Fcg receptor expression and antibody pharmacokinetics will improve the preclinical assessment of antibody-based therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE261975 | GEO | 2025/09/01

REPOSITORIES: GEO

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