The Dual Targeting of FcRn and FcγRs via Monomeric Fc Fragments Results in Strong Inhibition of IgG-Dependent Autoimmune Pathologies
Autor: | Nicholas C. Masiello, Aurélie Bauduin, Nathalie Fournier, Frederic Dhainaut, Alexander Seifert, Alain Longue, Anais Raia, Michel Nogre, Aurélie Terrier, Anais Engrand, Cécile Beghin, Gilles Dupont, Laetitia Danino, Alexandre Fontayne, Philippe Mondon, Emilie Jacque, Toufik Abache, Dieudonnée Togbe, Falk Nimmerjahn, Carmen Reitinger, Sami Chtourou, Delphine Derache, Wil Stevens, Louis Fauconnier, Céline Monnet, Christophe De Romeuf |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Platelet Aggregation
autoantibodies THP-1 Cells Autoimmunity Receptors Fc Protein Engineering Immunoglobulin G Jurkat Cells Immunology and Allergy Receptor Original Research Secretory Pathway biology immune complex (IC) Chemistry Cell biology Antirheumatic Agents Female Antibody Cell activation Protein Binding Signal Transduction medicine.drug_class Fc gamma receptor (FcγR) Immunology Fc engineering autoimmune disease Complement C5a Mice Transgenic Monoclonal antibody Binding Competitive Immune system Neonatal Fc receptor Phagocytosis medicine Animals Humans ddc:610 Fc fragment Autoimmune disease Histocompatibility Antigens Class I Receptors IgG RC581-607 medicine.disease Arthritis Experimental Immunoglobulin Fc Fragments Mice Inbred C57BL FcRn Kinetics Mutation biology.protein Interleukin-2 Immunologic diseases. Allergy |
Zdroj: | Frontiers in Immunology Frontiers in Immunology, Vol 12 (2021) |
ISSN: | 1664-3224 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |