The Dual Targeting of FcRn and FcγRs via Monomeric Fc Fragments Results in Strong Inhibition of IgG-Dependent Autoimmune Pathologies

Monnet C, Jacque E, de Romeuf C, Fontayne A, Abache T, Fournier N, Dupont G, Derache D, Engrand A, Bauduin A, Terrier A, Seifert A, Beghin C, Longue A, Masiello N, Danino L, Nogre M, Raia A, Dhainaut F, Fauconnier L, Togbe D, Reitinger C, Nimmerjahn F, Stevens W, Chtourou S, Mondon P (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Frontiers in Immunology Frontiers Research Foundation / Frontiers Media

Book Volume: 12

Article Number: 728322

DOI: 10.3389/fimmu.2021.728322

Abstract

Novel molecules that directly target the neonatal Fc receptor (FcRn) and/or Fc gamma receptors (FcγRs) are emerging as promising treatments for immunoglobulin G (IgG)-dependent autoimmune pathologies. Mutated Fc regions and monoclonal antibodies that target FcRn are currently in clinical development and hold promise for reducing the levels of circulating IgG. Additionally, engineered structures containing multimeric Fc regions allow the dual targeting of FcRn and FcγRs; however, their tolerance needs to first be validated in phase I clinical studies. Here, for the first time, we have developed a modified monomeric recombinant Fc optimized for binding to all FcRns and FcγRs without the drawback of possible tolerance associated with FcγR cross-linking. A rational approach using Fc engineering allowed the selection of LFBD192, an Fc with a combination of six mutations that exhibits improved binding to human FcRn and FcγR as well as mouse FcRn and FcγRIV. The potency of LFBD192 was compared with that of intravenous immunoglobulin (IVIg), an FcRn blocker (Fc-MST-HN), and a trimeric Fc that blocks FcRn and/or immune complex-mediated cell activation through FcγR without triggering an immune reaction in several in vitro tests and validated in three mouse models of autoimmune disease.

Authors with CRIS profile

Carmen Reitinger Lehrstuhl für Genetik Falk Nimmerjahn Lehrstuhl für Genetik

Involved external institutions

Laboratoire français du Fractionnement et des Biotechnologies (LFB SA) FR France (FR)

How to cite

APA:

Monnet, C., Jacque, E., de Romeuf, C., Fontayne, A., Abache, T., Fournier, N.,... Mondon, P. (2021). The Dual Targeting of FcRn and FcγRs via Monomeric Fc Fragments Results in Strong Inhibition of IgG-Dependent Autoimmune Pathologies. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.728322

MLA:

Monnet, Céline, et al. "The Dual Targeting of FcRn and FcγRs via Monomeric Fc Fragments Results in Strong Inhibition of IgG-Dependent Autoimmune Pathologies." Frontiers in Immunology 12 (2021).

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