Application of knockout mouse models to investigate the influence of FcγR on the tissue distribution and elimination of 8C2, a murine IgG1 monoclonal antibody

The current work examines the role of Fc gamma-receptors on the elimination and tissue distribution of 8C2, a model murine IgG1 monoclonal antibody. The plasma pharmacokinetics of (125)Iodine-labeled 8C2 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, 0.1 and 0.4 mg/kg. Plasma samples were collected and radioactivity was counted. Concentration data were analyzed with a population pharmacokinetic model. Additionally, the tissue disposition of 8C2 was investigated using whole body autoradioluminography (WBAL) and via counting excised tissues. Areas under the plasma concentration vs. time curves AUC(0-10 days) +/- SD (nM x days) were: 12.3 +/- 0.3, 12.5 +/- 1.3 and 15.1 +/- 1.2 at 0.04 mg/kg; 39.3 +/- 2.0, 28.9 +/- 2.7 and 42.0 +/- 9.4 at 0.1 mg/kg; and 225 +/- 19, 158 +/- 19 and 204 +/- 26 at 0.4 mg/kg in C57BL/6, Fc gamma RI/RIII(-/-) and Fc gamma RIIb(-/-) mice. Strain was not a statistically significant predictor for any of the parameters of the population model. 8C2 plasma clearance, distribution clearance, and central compartment volume were 0.00543 L/days/kg, 0.0598 L/days/kg, and 0.057 L/kg. No substantial differences in 8C2 tissue uptake were identified by analysis of excised tissues or by WBAL. In conclusion, Fc gamma R knockout is associated with only minor effects on the plasma and tissue disposition of 8C2, a model murine IgG1 mAb. (C) 2012 Published by Elsevier B. V.