7Q15

Crystal structure of FcRn and beta-2-microglobulin in complex with IgG1-Fc-MST-HN (efgartigimod)

Summary for 7Q15

• Entry DOI: 10.2210/pdb7q15/pdb
• Descriptor: IgG receptor FcRn large subunit p51, Beta-2-microglobulin, IgG1-Fc-MST-HN, ... (5 entities in total)
• Functional Keywords: neonatal fc receptor fcrn, fcrn, fc, igg1-fc-mst-hn, efgartigimod, argx-113, fcrn-binding protein, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 155950.13

Authors

Pannecoucke, E.,Savvides, S.N. (deposition date: 2021-10-18, release date: 2022-09-28, Last modification date: 2024-11-06)

Primary citation

Brinkhaus, M.,Pannecoucke, E.,van der Kooi, E.J.,Bentlage, A.E.H.,Derksen, N.I.L.,Andries, J.,Balbino, B.,Sips, M.,Ulrichts, P.,Verheesen, P.,de Haard, H.,Rispens, T.,Savvides, S.N.,Vidarsson, G.
The Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement.
Nat Commun, 13:6073-6073, 2022

PubMed 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.

PubMed: 36241613
DOI: 10.1038/s41467-022-33764-1

Experimental method

X-RAY DIFFRACTION (3.301 Å)