The Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement

• DOI: 10.1038/s41467-022-33764-1
• Publication Date: 2022-10-14T10:03:04Z
• Authors: Maximilian Brinkhaus; Erwin Pannecoucke; Elvera J. van der...; Arthur E. H. Bent...; Ninotska I. L. De...; Julie Andries; Bianca Balbino; Magdalena Sips; Peter Ulrichts; Peter Verheesen; Hans de Haard; Theo Rispens; Savvas N. Savvides; Gestur Vidarsson
• Keywords: Neonatal Fc receptor; Internalization; Fragment crystallizable region; Immunoglobulin Fc Fragments

Abstract Binding to the neonatal Fc receptor (FcRn) extends serum half-life of IgG, and antagonizing this interaction is a promising therapeutic approach in IgG-mediated autoimmune diseases. Fc-MST-HN, designed for enhanced FcRn binding capacity, has not been evaluated context full-length antibody, structural properties attached Fab regions might affect FcRn-mediated intracellular trafficking pathway. Here we present comprehensive comparative analysis IgG salvage pathway between two full-size IgG1 variants, containing wild type MST-HN fragments, their Fc-only counterparts. We find no evidence Fab-regions affecting cell-free assays, however, cellular assays show impaired FcRn, which translates into improved occupancy accumulation Fc-MST-HN compared full size IgG1-MST-HN. The crystal structure complex with provides plausible explanation why disrupts only membrane-associated FcRn. Importantly, that outperforms IgG1-MST-HN reducing levels cynomolgus monkeys. Collectively, our findings identify membrane as critical factor biology targeting.