PMID- 34512662
OWN - NLM
STAT- MEDLINE
DCOM- 20211227
LR  - 20240226
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - The Dual Targeting of FcRn and FcgammaRs via Monomeric Fc Fragments Results in Strong 
      Inhibition of IgG-Dependent Autoimmune Pathologies.
PG  - 728322
LID - 10.3389/fimmu.2021.728322 [doi]
LID - 728322
AB  - Novel molecules that directly target the neonatal Fc receptor (FcRn) and/or Fc 
      gamma receptors (FcgammaRs) 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 
      FcgammaRs; 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 FcgammaRs without the drawback 
      of possible tolerance associated with FcgammaR 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 FcgammaR as well as 
      mouse FcRn and FcgammaRIV. 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 FcgammaR 
      without triggering an immune reaction in several in vitro tests and validated in 
      three mouse models of autoimmune disease.
CI  - Copyright (c) 2021 Monnet, Jacque, de Romeuf, Fontayne, Abache, Fournier, Dupont, 
      Derache, Engrand, Bauduin, Terrier, Seifert, Beghin, Longue, Masiello, Danino, 
      Nogre, Raia, Dhainaut, Fauconnier, Togbe, Reitinger, Nimmerjahn, Stevens, 
      Chtourou and Mondon.
FAU - Monnet, Celine
AU  - Monnet C
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Jacque, Emilie
AU  - Jacque E
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - de Romeuf, Christophe
AU  - de Romeuf C
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Fontayne, Alexandre
AU  - Fontayne A
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Abache, Toufik
AU  - Abache T
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Fournier, Nathalie
AU  - Fournier N
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Dupont, Gilles
AU  - Dupont G
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Derache, Delphine
AU  - Derache D
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Engrand, Anais
AU  - Engrand A
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Bauduin, Aurelie
AU  - Bauduin A
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Terrier, Aurelie
AU  - Terrier A
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Seifert, Alexander
AU  - Seifert A
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Beghin, Cecile
AU  - Beghin C
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Longue, Alain
AU  - Longue A
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Masiello, Nicholas
AU  - Masiello N
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Danino, Laetitia
AU  - Danino L
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Nogre, Michel
AU  - Nogre M
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Raia, Anais
AU  - Raia A
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Dhainaut, Frederic
AU  - Dhainaut F
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Fauconnier, Louis
AU  - Fauconnier L
AD  - Artimmune, Orleans, France.
FAU - Togbe, Dieudonnee
AU  - Togbe D
AD  - Artimmune, Orleans, France.
FAU - Reitinger, Carmen
AU  - Reitinger C
AD  - Division of Genetics, Department of Biology, Friedrich-Alexander University 
      Erlangen-Nurnberg, Erlangen, Germany.
FAU - Nimmerjahn, Falk
AU  - Nimmerjahn F
AD  - Division of Genetics, Department of Biology, Friedrich-Alexander University 
      Erlangen-Nurnberg, Erlangen, Germany.
FAU - Stevens, Wil
AU  - Stevens W
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Chtourou, Sami
AU  - Chtourou S
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
FAU - Mondon, Philippe
AU  - Mondon P
AD  - LFB Biotechnologies, Innovation Department, Les Ulis, France.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210826
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (IL2 protein, human)
RN  - 0 (Immunoglobulin Fc Fragments)
RN  - 0 (Interleukin-2)
RN  - 0 (Receptors, Fc)
RN  - 0 (Receptors, IgG)
RN  - 80295-54-1 (Complement C5a)
RN  - TW3XAW0RCY (Fc receptor, neonatal)
SB  - IM
MH  - Animals
MH  - Antirheumatic Agents/metabolism/*pharmacology
MH  - Arthritis, Experimental/genetics/immunology/metabolism/*prevention & control
MH  - Autoimmunity/*drug effects
MH  - Binding, Competitive
MH  - Complement C5a/metabolism
MH  - Female
MH  - Histocompatibility Antigens Class I/genetics/immunology/metabolism
MH  - Humans
MH  - Immunoglobulin Fc Fragments/genetics/immunology/metabolism/*pharmacology
MH  - Interleukin-2/metabolism
MH  - Jurkat Cells
MH  - Kinetics
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Mutation
MH  - Phagocytosis/drug effects
MH  - Platelet Aggregation/drug effects
MH  - Protein Binding
MH  - Protein Engineering
MH  - Receptors, Fc/*antagonists & inhibitors/genetics/immunology/metabolism
MH  - Receptors, IgG/*antagonists & inhibitors/genetics/immunology/metabolism
MH  - Secretory Pathway
MH  - Signal Transduction
MH  - THP-1 Cells
MH  - Mice
PMC - PMC8427755
OTO - NOTNLM
OT  - Fc engineering
OT  - Fc fragment
OT  - Fc gamma receptor (FcgammaR)
OT  - FcRn
OT  - autoantibodies
OT  - autoimmune disease
OT  - immune complex (IC)
COIS- Authors CM, EJ, CRe, AF, TA, NF, GD, DD, AE, AB, AT, AS, CB, AL, NM, LD, MN, AR, 
      FD, WS, SC and PM are employees of LFB Biotechnologies, which patented the 
      described Fc mutations. DT and LF are employees of Artimmune. The remaining 
      authors declare that the research was conducted in the absence of any commercial 
      or financial relationships that could be construed as a potential conflict of 
      interest.
EDAT- 2021/09/14 06:00
MHDA- 2021/12/28 06:00
PMCR- 2021/01/01
CRDT- 2021/09/13 06:44
PHST- 2021/06/21 00:00 [received]
PHST- 2021/08/09 00:00 [accepted]
PHST- 2021/09/13 06:44 [entrez]
PHST- 2021/09/14 06:00 [pubmed]
PHST- 2021/12/28 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.728322 [doi]
PST - epublish
SO  - Front Immunol. 2021 Aug 26;12:728322. doi: 10.3389/fimmu.2021.728322. eCollection 
      2021.