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

摘要

This work evaluates the influence of Fc??R on the pharmacokinetics and pharmacodynamics of a rat anti-integrin-??IIb IgG1 monoclonal antibody, MWReg30, in mice. The pharmacokinetics and pharmacodynamics of MWReg30 were investigated in C57BL/6 control mice, Fc??RI/RIII knockout mice, and Fc??RIIb knockout mice, following intravenous doses of 0.04-0.4 mg/kg. MWReg30 treatment resulted in a dose-dependent induction of thrombocytopenia in all strains, but sensitivity to MWReg30 was increased in Fc??RIIb knockout mice and decreased in Fc??RI/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 0.05 mg/kg, 28.4 ?? 13.7, 56.7 ?? 5.1, and 20.6 ?? 9.5% at 0.2 mg/kg, and 24.9 ?? 7.2, 38.7 ?? 7.5, and 7.4 ?? 2.2% at 0.4 mg/kg in control, Fc??RI/RIII(-/-) and Fc??RIIb(-/-) mice. However, knocking out Fc??R 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 0.04 mg/kg, and 12.7 ?? 0.5, 13.6 ?? 1.1, and 14.5 ?? 2.0 nM ?? d at 0.1 mg/kg in control, Fc??RI/RIII(-/-) and Fc??RIIb(-/-) mice. The findings further emphasize the role of activating vs. inhibitory Fc??R in processing immune complexes (i.e.; MWReg30-platelets), while also providing an example where monoclonal antibody pharmacokinetics are not substantially influenced by Fc??R expression. ? 2013 Elsevier B.V. All rights reserved.