FcγR humanized mouse models enabling efficacy and PK/PD of therapeutic antibodies

Background

Enhanced activity of therapeutic IgG can be achieved by the modulation of Fc binding to Fcγ receptors (FcγR) which consequently modulate the Fc-effector function triggered upon crosslinking of target and effector cells by these antibodies. Assessment of therapeutic antibodies’ pharmacodynamics in preclinical models is challenging, as the FcγR differ between mice and human, as well as in their expression pattern. Humanized FcγR (hFcγR) model features a human-like expression pattern, in which humanized FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, FcγRIIIB are expressed and replace their mouse orthologs. We have previously reported that humanized FcγR expression pattern in hFcγR mice is consistent with their expression on human PBMC, with a few exceptions. Test of antibody-dependent cell cytotoxicity (ADCC) ex vivo in NK cells showed that Rituximab, an anti-hCD20 chimeric IgG1 with regular Fc, induces higher ADCC efficacy in NK cells from hFcγR than in NK cells from WT mice. Obinutuzumab, which also targets hCD20, but features an optimized Fc portion to enhance binding to FcγRIII, showed higher tumor cell lysis than Rituximab in NK cells from hFcγR mice, suggesting this model enables the ranking of antibodies.