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

Autor: Brinkhaus M; Immunoglobulin Research Laboratory, Department of Experimental Immunohematology, Sanquin Research and Landsteiner, Amsterdam UMC, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands.; Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.; argenx, 9052, Zwijnaarde, Belgium., Pannecoucke E; argenx, 9052, Zwijnaarde, Belgium.; Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, 9052, Ghent, Belgium.; Unit for Structural Biology, VIB-UGent Center for Inflammation Research, 9052, Ghent, Belgium., van der Kooi EJ; Immunoglobulin Research Laboratory, Department of Experimental Immunohematology, Sanquin Research and Landsteiner, Amsterdam UMC, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands.; Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands., Bentlage AEH; Immunoglobulin Research Laboratory, Department of Experimental Immunohematology, Sanquin Research and Landsteiner, Amsterdam UMC, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands.; Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands., Derksen NIL; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands., Andries J; Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, 9052, Ghent, Belgium.; Unit for Structural Biology, VIB-UGent Center for Inflammation Research, 9052, Ghent, Belgium., Balbino B; argenx, 9052, Zwijnaarde, Belgium., Sips M; argenx, 9052, Zwijnaarde, Belgium., Ulrichts P; argenx, 9052, Zwijnaarde, Belgium., Verheesen P; argenx, 9052, Zwijnaarde, Belgium., de Haard H; argenx, 9052, Zwijnaarde, Belgium., Rispens T; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands., Savvides SN; Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, 9052, Ghent, Belgium.; Unit for Structural Biology, VIB-UGent Center for Inflammation Research, 9052, Ghent, Belgium., Vidarsson G; Immunoglobulin Research Laboratory, Department of Experimental Immunohematology, Sanquin Research and Landsteiner, Amsterdam UMC, University of Amsterdam, 1066 CX, Amsterdam, The Netherlands. G.vidarsson@sanquin.nl.; Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands. G.vidarsson@sanquin.nl.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Oct 14; Vol. 13 (1), pp. 6073. Date of Electronic Publication: 2022 Oct 14.
DOI: 10.1038/s41467-022-33764-1
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: