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

Abstract

The current work examines the role of Fcγ-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, FcγRI/RIII knockout mice, and FcγRIIb 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×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, FcγRI/RIII(-/-) and FcγRIIb(-/-) 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, FcγR knockout is associated with only minor effects on the plasma and tissue disposition of 8C2, a model murine IgG1 mAb.