PMID- 33823154
OWN - NLM
STAT- MEDLINE
DCOM- 20210713
LR  - 20221207
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 296
DP  - 2021 Jan-Jun
TI  - A novel anti-human IL-1R7 antibody reduces IL-18-mediated inflammatory signaling.
PG  - 100630
LID - S0021-9258(21)00416-6 [pii]
LID - 10.1016/j.jbc.2021.100630 [doi]
LID - 100630
AB  - Unchecked inflammation can result in severe diseases with high mortality, such as 
      macrophage activation syndrome (MAS). MAS and associated cytokine storms have 
      been observed in COVID-19 patients exhibiting systemic hyperinflammation. 
      Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, 
      is elevated in both MAS and COVID-19 patients, and its level is known to 
      correlate with the severity of COVID-19 symptoms. IL-18 binds its specific 
      receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), 
      leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known 
      as IL-18 receptor beta chain). This heterotrimeric complex then initiates 
      downstream signaling, resulting in systemic and local inflammation. Here, we 
      developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block 
      the activity of IL-18 and its inflammatory signaling. We characterized the 
      function of this antibody in human cell lines, in freshly obtained peripheral 
      blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that 
      the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFkappaB activation, 
      reduced IL-18-stimulated IFNgamma and IL-6 production in human cell lines, and 
      reduced IL-18-induced IFNgamma, IL-6, and TNFalpha production in PBMCs. Moreover, the 
      anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans-induced 
      IFNgamma production in PBMCs, as well as LPS-induced IFNgamma production in whole blood 
      cultures. Our data suggest that blocking IL-1R7 could represent a potential 
      therapeutic strategy to specifically modulate IL-18 signaling and may warrant 
      further investigation into its clinical potential for treating IL-18-mediated 
      diseases, including MAS and COVID-19.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Li, Suzhao
AU  - Li S
AD  - Department of Medicine, University of Colorado Denver Anschutz Medical Campus, 
      Aurora, Colorado, USA. Electronic address: suzhao.li@cuanschutz.edu.
FAU - Jiang, Liqiong
AU  - Jiang L
AD  - Department of Medicine, University of Colorado Denver Anschutz Medical Campus, 
      Aurora, Colorado, USA; Shenzhen Eye Hospital, Shenzhen, Guangdong, China.
FAU - Beckmann, Karsten
AU  - Beckmann K
AD  - MAB Discovery GmbH, Neuried, Germany.
FAU - Hojen, Jesper Falkesgaard
AU  - Hojen JF
AD  - Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
FAU - Pessara, Ulrich
AU  - Pessara U
AD  - MAB Discovery GmbH, Neuried, Germany.
FAU - Powers, Nicholas E
AU  - Powers NE
AD  - Department of Medicine, University of Colorado Denver Anschutz Medical Campus, 
      Aurora, Colorado, USA.
FAU - de Graaf, Dennis M
AU  - de Graaf DM
AD  - Department of Medicine, University of Colorado Denver Anschutz Medical Campus, 
      Aurora, Colorado, USA.
FAU - Azam, Tania
AU  - Azam T
AD  - Department of Medicine, University of Colorado Denver Anschutz Medical Campus, 
      Aurora, Colorado, USA.
FAU - Lindenberger, Jared
AU  - Lindenberger J
AD  - Biophysics Core Facility, University of Colorado Denver Anschutz Medical Campus, 
      Aurora, Colorado, USA.
FAU - Eisenmesser, Elan Z
AU  - Eisenmesser EZ
AD  - Department of Biochemistry and Molecular Genetics, University of Colorado Denver 
      Anschutz Medical Campus, Aurora, Colorado, USA.
FAU - Fischer, Stephan
AU  - Fischer S
AD  - MAB Discovery GmbH, Neuried, Germany.
FAU - Dinarello, Charles A
AU  - Dinarello CA
AD  - Department of Medicine, University of Colorado Denver Anschutz Medical Campus, 
      Aurora, Colorado, USA. Electronic address: cdinare333@aol.com.
LA  - eng
GR  - R03 AI151651/AI/NIAID NIH HHS/United States
GR  - R01 AI015614/AI/NIAID NIH HHS/United States
GR  - R56 AI015614/AI/NIAID NIH HHS/United States
GR  - R03 AI156560/AI/NIAID NIH HHS/United States
GR  - R21 AI128443/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210403
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (IL6 protein, human)
RN  - 0 (Immunologic Factors)
RN  - 0 (Interleukin-18)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Receptors, Interleukin-18)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Anti-Inflammatory Agents/metabolism/*pharmacology
MH  - Antibodies, Monoclonal/biosynthesis/*pharmacology
MH  - Antibodies, Neutralizing/biosynthesis/*pharmacology
MH  - Candida albicans/growth & development/pathogenicity
MH  - Gene Expression Regulation
MH  - HEK293 Cells
MH  - Humans
MH  - Immunologic Factors/biosynthesis/*pharmacology
MH  - Inflammation
MH  - Interferon-gamma/genetics/immunology
MH  - Interleukin-18/*genetics/immunology
MH  - Interleukin-6/genetics/immunology
MH  - Leukocytes, Mononuclear/drug effects/immunology/microbiology
MH  - Lipopolysaccharides/antagonists & inhibitors/pharmacology
MH  - Macrophage Activation Syndrome/drug therapy
MH  - NF-kappa B/genetics/immunology
MH  - Primary Cell Culture
MH  - Receptors, Interleukin-18/antagonists & inhibitors/*genetics/immunology
MH  - SARS-CoV-2/immunology/pathogenicity
MH  - Signal Transduction/drug effects
MH  - Tumor Necrosis Factor-alpha/genetics/immunology
MH  - COVID-19 Drug Treatment
PMC - PMC8018910
OTO - NOTNLM
OT  - COVID-19
OT  - IFNgamma
OT  - IL-1 receptor 7 (IL-1R7)
OT  - blockade
OT  - interleukin-18 (IL-18)
OT  - macrophage activation syndrome (MAS)
OT  - therapeutic
COIS- Conflict of interest K. B. and U. P. were employed by MAB Discovery GmbH, 
      Neuried, Germany. S. F. is the CEO of MAB Discovery GmbH. J. F. H. has received 
      consulting fees from MAB Discovery GmbH. Other authors declare that they have no 
      conflicts of interest with the contents of this article.
EDAT- 2021/04/07 06:00
MHDA- 2021/07/14 06:00
PMCR- 2021/04/03
CRDT- 2021/04/06 20:08
PHST- 2020/11/19 00:00 [received]
PHST- 2021/03/29 00:00 [revised]
PHST- 2021/04/01 00:00 [accepted]
PHST- 2021/04/07 06:00 [pubmed]
PHST- 2021/07/14 06:00 [medline]
PHST- 2021/04/06 20:08 [entrez]
PHST- 2021/04/03 00:00 [pmc-release]
AID - S0021-9258(21)00416-6 [pii]
AID - 100630 [pii]
AID - 10.1016/j.jbc.2021.100630 [doi]
PST - ppublish
SO  - J Biol Chem. 2021 Jan-Jun;296:100630. doi: 10.1016/j.jbc.2021.100630. Epub 2021 
      Apr 3.