Translational modelling from preclinical data to predict human PK of monoclonal antibodies with engineered FcRn binding
Authors: Vollmer Jannik , Machacek Matthias 
Published: February 2025

Objectives: Targeted modification the Fc region such as the M428L/N434S (LS) and M252Y/S254T/T256E (YTE) mutations are used to improve the plasma half-life of monoclonal antibodies (mAb). A systematic, model-based assessment of how these mutations impact half-life and how preclinical species' pharmacokinetics (PK) can be extrapolated to humans has not existed. The objectives of this study were to characterize the effect of LS and YTE mutations on the PK properties across mouse, cynomolgus monkey (NHP) and human and to establish the interspecies scaling of the PK parameters. Methods: PK profiles for compounds with LS or YTE mutations in hFcRn mice, NHP, and humans were compiled from the literature. Where available, PK profiles from the parental compounds with wild type Fc regions were included. mAb distribution and elimination was described with a 2-compartmental PK model. Between animal variability, the observational error and the effects of LS and YTE mutations on the PK parameter were described with a non-linear mixed effects model. Log-normal distributed individual parameters and a combined error model were used. Population parameters were estimated with Monolix 2023R1. The Fc mutation was used as a categorical covariate on clearance. Body weight based allometric scaling was assumed for all PK parameters. Results: The dataset for the analysis consisted of 22 different mAbs. For some of the compounds PK profiles were available in multiple species and/or at multiple dose levels. Species-specific and combined-species PK parameters were estimated. PK parameter estimates were largely within the expected range. The central volume of distribution for human (32.6 mL/kg) and NHP (34.6 mL/kg) was slightly smaller than expected when using the plasma volume as reference (40 mL/kg). BW-based allometric scaling coefficients in the combined-species model were 0.96 for V1, 1.02 for V2, 0.76 for Q and 0.73 for CL. Fc variant was found to be a statistically significant covariate on CL but on none of the other PK parameters. The estimated increase of the terminal elimination half-life in human was 2.9- to 3.9-fold for the LS mutation and 3.5- to 5.0-fold for the YTE mutation. Conclusions: Our findings demonstrate that for Fc-mutated antibodies body weight-based allometric scaling from hFcRn mice or NHP was predictive for human. The identified allometric scaling coefficients closely align with standard scaling coefficients previously reported for mAbs. Interestingly, the estimated scaling coefficient for clearance of 0.73 was slightly lower than previous estimates of 0.8 to 0.93 [1,2]. Notably, we identified that the LS and YTE mutations significantly reduce clearance but had no significant impact on mAb distribution. The effect of the LS and YTE mutations on clearance were similar. This analysis provides a foundation for predicting PK in preclinical species and, potentially more critically, in humans for IgG molecules carrying the LS or YTE mutation.Citations: [1] Avery LB, Wang M, Kavosi MS, Joyce A, Kurz JC, Fan YY, Dowty ME, Zhang M, Zhang Y, Cheng A, Hua F, Jones HM, Neubert H, Polzer RJ, O'Hara DM. Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies. MAbs. 2016 Aug-Sep;8(6):1064-78. doi: 10.1080/19420862.2016.1193660. Epub 2016 May 27. PMID: 27232760; PMCID: PMC4968115. [2] Betts A, Keunecke A, van Steeg TJ, van der Graaf PH, Avery LB, Jones H, Berkhout J. Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach. MAbs. 2018 Jul;10(5):751-764. doi: 10.1080/19420862.2018.1462429. Epub 2018 May 14. PMID: 29634430; PMCID: PMC6150614.