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
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