Humanized FcRn mouse models for evaluating pharmacokinetics of human IgG antibodies

Abstract

A key element for the successful development of novel therapeutic antibodies is to fully understand their pharmacokinetic and pharmacodynamic behavior before performing clinical trials. While many in vitro modeling approaches exist, these simply cannot substitute for data obtained from appropriate animal models. It was established quite early that the unusual long serum half-life of immunoglobulin G’s (IgGs) and Fc domains are due to their rescue and recycling by the neonatal Fc receptor (FcRn). The diverse roles of FcRn became apparent after isolation and cloning. Interesting are the significant species differences between rodent and human FcRn reactivity, rendering wild type rodents an inadequate model for studying IgG serum half-life. With the advance of genetic engineering mouse models have been established expressing human FcRn, and lacking mouse FcRn protein. These models have become highly relevant tools for serum half-life analysis of Fc-containing compounds.

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

“…It has been determined that the FcRn is responsible for the active transport of molecules containing an Fc domain across the blood retinal barrier and it therefore increases the overall bioavailability. This makes the FcRn clinically relevant not only for the intra-ocular pharmacokinetics of therapeutic monoclonal antibodies, but also for the offtarget effect on VEGF in the periphery by actively transporting the anti-VEGF agents from the vitreous into the systemic circulation (Roopenian & Akilesh 2007;Powner et al 2014;Proetzel & Roopenian 2014). Upon reaching the blood stream, the duration of the anti-VEGF effect is contingent on its systemic half-life.…”

Combined glyco- and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody

“…These FcRn-humanized mice, unlike wild-type mice, have been shown to be a reliable surrogate for studying human IgG serum half-life. 23,53 Despite reduced circulating murine IgGs, these humanized mice reliably predicted antibody half-lives in primates when challenged with clinical mAbs for which PK data were available. 54 Moreover, whereas human IgG binding and pH dependency are highly similar for human and monkey FcRn, human and murine FcRn have significant molecular differences rendering wild-type mice an inadequate model for studying half-life of engineered human IgGs.…”

Tissue expression profile of human neonatal Fc receptor (FcRn) in Tg32 transgenic mice

“…15 The results showed no detectable differences in half-lives between Tg32 and Tg32/hb 2 m mice, indicating functional human-mouse hybrid FcRn complexes were formed in the Tg32 transgenic mice systems. 15 PK studies in Tg32 hemizygous mice also showed high correlation of antibody clearance to human (Pearson r D 0.99, p< 0.001), suggesting that Tg32 could serve as an animal model for translational PK of Fc-containing biotherapeutics. 16 Therefore, establishing a quantitative hFcRn protein tissue expression profile in Tg32 will provide a key parameter for translational PBPK models for human PK predictions.…”