Application of knockout mouse models to investigate the influence of FcγR on the pharmacokinetics and anti-platelet effects of MWReg30, a monoclonal anti-GPIIb antibody

Abstract

This work evaluates the influence of FcγR on the pharmacokinetics and pharmacodynamics of a rat anti-integrin-αIIb IgG1 monoclonal antibody, MWReg30, in mice. The pharmacokinetics and pharmacodynamics of MWReg30 were investigated in C57BL/6 control mice, FcγRI/RIII knockout mice, and FcγRIIb knockout mice, following intravenous doses of 0.04-0.4mg/kg. MWReg30 treatment resulted in a dose-dependent induction of thrombocytopenia in all strains, but sensitivity to MWReg30 was increased in FcγRIIb knockout mice and decreased in FcγRI/RIII knockout mice, relative to results found in control mice. Expressed as a percentage of pre-treatment platelet counts, nadir platelet counts were 28.6±5.0, 88.7±16.6 and 25.3±6.1% at 0.05mg/kg, 28.4±13.7, 56.7±5.1, and 20.6±9.5% at 0.2mg/kg, and 24.9±7.2, 38.7±7.5, and 7.4±2.2% at 0.4mg/kg in control, FcγRI/RIII(-/-) and FcγRIIb(-/-) mice. However, knocking out FcγR did not affect MWReg30 pharmacokinetics. Plasma areas under the concentration vs. time curves (AUC0-10 days) ±SD for MWReg30 were: 5.24±0.68, 5.51±0.24, and 5.39±1.05 nM×d at 0.04mg/kg, and 12.7±0.5, 13.6±1.1, and 14.5±2.0nM×d at 0.1mg/kg in control, FcγRI/RIII(-/-) and FcγRIIb(-/-) mice. The findings further emphasize the role of activating vs. inhibitory FcγR in processing immune complexes (i.e., MWReg30-platelets), while also providing an example where monoclonal antibody pharmacokinetics are not substantially influenced by FcγR expression.