Characterization of the immunological responses in a mouse model expressing humanized FcγR/FcRn

Background: Therapeutic antibodies have revolutionized cancer treatment by leveraging immune mechanisms such as Fc-effector functions, which depend on interactions between IgG and Fcγ receptors (FcγR). However, preclinical evaluation of antibody pharmacokinetics (PK) and pharmacodynamics (PD) remains challenging due to species-specific differences in FcγR and FcRn expression and function. We previously reported a FcγR humanized model that expresses a human-like pattern of FcγRs (including FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA and FcγRIIIB – genO-hFcγR). These receptors are functional and enable accurate evaluation of Fc-effector functions such as ADCC and B-cell depletion. The model demonstrated Fc-dependent activity of therapeutic IgG, allowing differentiation between antibodies with regular versus enhanced FcγR binding and supports ranking of Fc-engineered antibodies in preclinical studies1. FcRn was also humanized in the model to enhance the translatability of PK studies by enabling human FcRn-mediated IgG recycling, while maintaining PD assessment of Fc-engineered therapeutic antibodies. Herein, we characterized the immunological competence of the humanized genO‑FcγR/FcRn mouse model under inflammatory conditions by comparing its immune responses with those of wild‑type (WT) mice following defined immunological challenges.

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