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

Frontiers in Immunology

Louis Fauconnier¹  Dieudonnée Togbe¹  Falk Nimmerjahn²  Carmen Reitinger²  Laetitia Danino³  Cécile Beghin³  Frederic Dhainaut³  Wil Stevens³  Gilles Dupont³  Alexandre Fontayne³  Toufik Abache³  Philippe Mondon³  Emilie Jacque³  Aurélie Bauduin³  Nathalie Fournier³  Michel Nogre³  Anais Engrand³  Alexander Seifert³  Sami Chtourou³  Nicholas Masiello³  Christophe de Romeuf³  Alain Longue³  Céline Monnet³  Delphine Derache³  Anais Raia³  Aurélie Terrier³ 

[1] Artimmune, Orléans, France;Division of Genetics, Department of Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany;LFB Biotechnologies, Innovation Department, Les Ulis, France;

关键词: FcRn;    Fc fragment;    Fc engineering;    autoantibodies;    autoimmune disease;    immune complex (IC);   

DOI  :  10.3389/fimmu.2021.728322

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown