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

Maximilian Brinkhaus, Erwin Pannecoucke, Elvera J. Kooi, Arthur E. H. Bentlage, Ninotska I. L. Derksen, Julie Andries, Bianca Balbino, Magdalena Sips, Peter Ulrichts, Peter Verheesen, Hans Haard, Theo Rispens, Savvas N. Savvides and Gestur Vidarsson ()
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Maximilian Brinkhaus: Amsterdam UMC, University of Amsterdam
Erwin Pannecoucke: argenx
Elvera J. Kooi: Amsterdam UMC, University of Amsterdam
Arthur E. H. Bentlage: Amsterdam UMC, University of Amsterdam
Ninotska I. L. Derksen: Amsterdam UMC, University of Amsterdam
Julie Andries: Ghent University
Bianca Balbino: argenx
Magdalena Sips: argenx
Peter Ulrichts: argenx
Peter Verheesen: argenx
Hans Haard: argenx
Theo Rispens: Amsterdam UMC, University of Amsterdam
Savvas N. Savvides: Ghent University
Gestur Vidarsson: Amsterdam UMC, University of Amsterdam

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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 in the context of a full-length antibody, and the structural properties of the attached Fab regions might affect the FcRn-mediated intracellular trafficking pathway. Here we present a comprehensive comparative analysis of the IgG salvage pathway between two full-size IgG1 variants, containing wild type and MST-HN Fc fragments, and their Fc-only counterparts. We find no evidence of Fab-regions affecting FcRn binding in cell-free assays, however, cellular assays show impaired binding of full-size IgG to FcRn, which translates into improved intracellular FcRn occupancy and intracellular accumulation of Fc-MST-HN compared to full size IgG1-MST-HN. The crystal structure of Fc-MST-HN in complex with FcRn provides a plausible explanation why the Fab disrupts the interaction only in the context of membrane-associated FcRn. Importantly, we find that Fc-MST-HN outperforms full-size IgG1-MST-HN in reducing IgG levels in cynomolgus monkeys. Collectively, our findings identify the cellular membrane context as a critical factor in FcRn biology and therapeutic targeting.

Date: 2022
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DOI: 10.1038/s41467-022-33764-1

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