Prediction of human pharmacokinetics of Fc-engineered therapeutic monoclonal antibodies using human FcRn transgenic mice.

Human FcRn transgenic mice (Tg32) have been widely used to evaluate the pharmacokinetics of mAbs and predict human pharmacokinetics. This study aims to establish an approach for predicting the human pharmacokinetics of Fc-engineered mAbs with enhanced FcRn binding mutations using Tg32 mice. MAbs were intravenously administered at 10 mg/kg in the absence or presence of IVIG (1000 mg/kg) in Tg32 mice. Pharmacokinetic parameters (CL, Q, V_c, and V_p) estimated in Tg32 mice were compared with clinical data. Optimal allometric scaling exponents were determined to improve the accuracy of human pharmacokinetic predictions for Fc-engineered mAbs. Moreover, we predicted the plasma concentration-time profile after IV injection in humans using parameters estimated based on an optimized exponent. While normal mAbs exhibited a higher CL in the presence of IVIG compared to its absence, Fc-engineered mAbs showed comparable CL in both conditions. The larger difference in CL between normal and Fc-engineered mAbs observed in the presence of IVIG closely matched clinical study results. A significant positive correlation between Tg32 mice and humans was observed in the CL of Fc-engineered mAbs in both the absence and presence of IVIG. The estimated optimal exponents for CL, Q, V_c, and V_p were 0.73, 0.60, 0.95, and 0.87, respectively. Using these exponents, the plasma mAb concentration-time profile after IV injection in humans was accurately predicted. This study establishes a robust methodology for accurately predicting the human pharmacokinetics of Fc-engineered mAbs using Tg32 mice, achieving prediction accuracy comparable to that of cynomolgus monkeys. This approach, as a viable alternative to cynomolgus monkeys, can accelerate the preclinical development of promising Fc-engineered mAbs with enhanced FcRn binding.