ReviewAre endosomal trafficking parameters better targets for improving mAb pharmacokinetics than FcRn binding affinity?

- Although many studies report that increasing the very high Fc-FcRn affinity at pH 6.0 increases mAb half-life, in fact the results are mixed.
- Studies have increasingly implicated non-FcRn determinants of mAb pharmacokinetics (PK), but predicting and tuning PK is not yet solved.
- It was never clear why the micro-molar saturating Brambell salvage mechanism benefitted from adjusting the nano-molar Fc-FcRn interaction.
- We propose that endosomal sorting and trafficking dynamics best explain both the high molarity saturation of mAb salvage and their PK differences.
- We review mAb endosomal trafficking and the latest physiologically based PK modelling in search of reproducible correlates of mAb half-life.

F.W.R. Brambell deduced the existence of a protective receptor for IgG, the neonatal Fc receptor (FcRn), long before its discovery in the early to mid-1990s. With the coincident, explosive development of IgG-based drugs, FcRn became a popular target for tuning the pharmacokinetics of monoclonal antibodies (mAbs). One aspect of Brambell's initial observation, however, that is seldom discussed since the discovery of the receptor, is the compliance in the mechanism that Brambell observed (saturating at 10s-100s of μM concentration), vs. the comparative stiffness of the receptor kinetics (saturating in the nM range for most species). Although some studies reported that increasing the already very high Fc-FcRn affinity at pH 6.0 further improved mAb half-life, in fact the results were mixed, with later studies increasingly implicating non-FcRn-dependent mechanisms as determinants of mAb pharmacokinetics. Mathematical modelling of the FcRn system has also indicated that the processes determining the pharmacokinetics of mAbs have more nuances than had at first been hypothesised. We propose, in keeping with the latest modelling and experimental evidence reviewed here, that the dynamics of endosomal sorting and trafficking have important roles in the compliant salvage mechanism that Brambell first observed nearly 50 years ago, and therefore also in the pharmacokinetics of mAbs. These ideas lead to many open questions regarding the endosomal trafficking of both FcRn and mAbs and also to what properties of a mAb can be altered to achieve an improvement in pharmacokinetics.