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 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.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, NY 14260, USA.
Lubna
L
Abuqayyas
Xiaoyan
X
Zhang
Joseph P
JP
Balthasar
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000494:pharmacology*; D010976:Platelet Count; D040201:Platelet Membrane Glycoprotein IIb / Q000276:immunology*; D017452:Receptors, IgG / Q000502:physiology*; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; C582819:MWReg30 monoclonal antibody; D010975:Platelet Aggregation Inhibitors; D040201:Platelet Membrane Glycoprotein IIb; D017452:Receptors, IgG