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

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.

• Authors: Maximilian Brinkhaus, Erwin Pannecoucke, Elvera J van der Kooi, Arthur E H Bentlage, Ninotska I L Derksen, Julie Andries, Bianca Balbino, Magdalena Sips, Peter Ulrichts, Peter Verheesen, Hans de Haard, Theo Rispens, Savvas N Savvides, Gestur Vidarsson
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 6073 (10 14 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 36241613 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Antibodies, Monoclonal
• Histocompatibility Antigens Class I
• Immunoglobulin Fc Fragments
• Immunoglobulin G
• Receptors, Fc

Topics

• Animals
• Antibodies, Monoclonal
• Autoimmune Diseases (drug therapy)
• Histocompatibility Antigens Class I
• Immunoglobulin Fc Fragments (chemistry)
• Immunoglobulin G
• Macaca fascicularis (metabolism)
• Protein Binding
• Receptors, Fc