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

This work evaluates the influence of Fc gamma R on the pharmacokinetics and pharmacodynamics of a rat anti-integrin-alpha IIb IgG1 monoclonal antibody, MWReg30, in mice. The pharmacokinetics and pharmacodynamics of MWReg30 were investigated in C57BL/6 control mice, Fc gamma RI/RIII knockout mice, and Fc gamma 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 gamma RIIb knockout mice and decreased in Fc gamma 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 gamma RI/RIII(-/-) and Fc gamma RIIb(-/-) mice. However, knocking out Fc gamma R did not affect MWReg30 pharmacokinetics. Plasma areas under the concentration vs. time curves (AUC(0-10 days)) +/- SD for MWReg30 were: 5.24 +/- 0.68, 5.51 +/- 0.24, and 5.39 +/- 1.05 nM x d at 0.04 mg/kg, and 12.7 +/- 0.5, 13.6 +/- 1.1, and 14.5 +/- 2.0 nM x d at 0.1 mg/kg in control, Fc gamma RI/RIII(-/-) and Fc gamma RIIb(-/-) mice. The findings further emphasize the role of activating vs. inhibitory Fc gamma R in processing immune complexes (i.e., MWReg30-platelets), while also providing an example where monoclonal antibody pharmacokinetics are not substantially influenced by Fc gamma R expression. (C) 2013 Elsevier B. V. All rights reserved.