In Translation: FcRn across the Therapeutic Spectrum

As an essential modulator of IgG disposition, the neonatal Fc receptor (FcRn) governs the pharmacokinetics and functions many therapeutic modalities. In this review, we thoroughly reexamine the hitherto elucidated biological and thermodynamic properties of FcRn to provide context for our assessment of more recent advances, which covers antigen-binding fragment (Fab) determinants of FcRn affinity, transgenic preclinical models, and FcRn targeting as an immune-complex (IC)-clearing strategy. We further comment on therapeutic antibodies authorized for treating SARS-CoV-2 (bamlanivimab, casirivimab, and imdevimab) and evaluate their potential to saturate FcRn-mediated recycling. Finally, we discuss modeling and simulation studies that probe the quantitative relationship between in vivo IgG persistence and in vitro FcRn binding, emphasizing the importance of endosomal transit parameters.

Automated summary

This review examines the biological and thermodynamic properties of FcRn and recent advancements in the field, including Fab determinants of FcRn affinity, transgenic preclinical models, and FcRn targeting for immune-complex clearance. It also evaluates the potential of therapeutic antibodies for SARS-CoV-2 to saturate FcRn-mediated recycling. The importance of endosomal transit parameters in the quantitative relationship between in vivo IgG persistence and in vitro FcRn binding is emphasized through modeling and simulation studies.