The Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 10 2022
14 10 2022
Historique:
received:
21
02
2022
accepted:
30
09
2022
entrez:
14
10
2022
pubmed:
15
10
2022
medline:
19
10
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36241613
doi: 10.1038/s41467-022-33764-1
pii: 10.1038/s41467-022-33764-1
pmc: PMC9568614
doi:
Substances chimiques
Antibodies, Monoclonal
0
Histocompatibility Antigens Class I
0
Immunoglobulin Fc Fragments
0
Immunoglobulin G
0
Receptors, Fc
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6073Informations de copyright
© 2022. The Author(s).
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