title: Are endosomal trafficking parameters better targets for improving mAb pharmacokinetics than FcRn binding affinity?
abstract: 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.
authors.affiliation: Chronic Viral Diseases Branch, Division of High-Consequence Pathogens and Pathology, National Centre for Emerging and Zoonotic Infectious Diseases, Centres for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: brian.gurbaxani@cdc.hhs.gov.
authors.forename: Brian
authors.initials: B
authors.lastname: Gurbaxani
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dostalek
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism / Q000493:pharmacokinetics; D000915:Antibody Affinity / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D018448:Models, Immunological; D011485:Protein Binding / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D011961:Receptors, Fc / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal
keywords: Da; Daltons; Endosome; F(ab’)(2); Fab; Fc; FcRn; Half-life; IgG; K(D); MW; Modelling; Monoclonal antibody; Neonatal Fc receptor; PBPK; Pharmacokinetics; SPR; Trafficking; binding rate; covalently bound Fab portions of an antibody; dissociation rate; equilibrium binding affinity; fragment crystallisable (antibody constant region); fragment with antigen binding (antibody variable region); immunoglobulin G; internalisation rate; k(int); k(off); k(on); k(rec); kDa; kilo Daltons; mAb; micrometer; micromolar; molecular weight; monoclonal antibody; nM; nanometer; nanomolar; negative log(10)concentration of solvated hydrogen ions/acidity; neonatal Fc receptor; nm; pH; physiologically based pharmacokinetics; recycling rate; surface plasmon resonance; μM; μm