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Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor

Interleukin-1 (IL-1) family cytokines are potent mediators of inflammation, acting to coordinate local and systemic immune responses to a wide range of stimuli. Aberrant signaling by IL-1 family cytokine members, however, is linked to myriad inflammatory syndromes, autoimmune conditions and cancers....

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Autores principales: Fields, James K., Kihn, Kyle, Birkedal, Gabriel S., Klontz, Erik H., Sjöström, Kjell, Günther, Sebastian, Beadenkopf, Robert, Forsberg, Göran, Liberg, David, Snyder, Greg A., Deredge, Daniel, Sundberg, Eric J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740070/
https://www.ncbi.nlm.nih.gov/pubmed/35003094
http://dx.doi.org/10.3389/fimmu.2021.779100
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author Fields, James K.
Kihn, Kyle
Birkedal, Gabriel S.
Klontz, Erik H.
Sjöström, Kjell
Günther, Sebastian
Beadenkopf, Robert
Forsberg, Göran
Liberg, David
Snyder, Greg A.
Deredge, Daniel
Sundberg, Eric J.
author_facet Fields, James K.
Kihn, Kyle
Birkedal, Gabriel S.
Klontz, Erik H.
Sjöström, Kjell
Günther, Sebastian
Beadenkopf, Robert
Forsberg, Göran
Liberg, David
Snyder, Greg A.
Deredge, Daniel
Sundberg, Eric J.
author_sort Fields, James K.
collection PubMed
description Interleukin-1 (IL-1) family cytokines are potent mediators of inflammation, acting to coordinate local and systemic immune responses to a wide range of stimuli. Aberrant signaling by IL-1 family cytokine members, however, is linked to myriad inflammatory syndromes, autoimmune conditions and cancers. As such, blocking the inflammatory signals inherent to IL-1 family signaling is an established and expanding therapeutic strategy. While several FDA-approved IL-1 inhibitors exist, including an Fc fusion protein, a neutralizing antibody, and an antagonist cytokine, none specifically targets the co-receptor IL-1 receptor accessory protein (IL-1RAcP). Most IL-1 family cytokines form productive signaling complexes by binding first to their cognate receptors – IL-1RI for IL-1α and IL-1β; ST2 for IL-33; and IL-36R for IL-36α, IL-36β and IL-36γ – after which they recruit the shared secondary receptor IL-1RAcP to form a ternary cytokine/receptor/co-receptor complex. Recently, IL-1RAcP was identified as a biomarker for both AML and CML. IL-1RAcP has also been implicated in tumor progression in solid tumors and an anti-IL1RAP antibody (nadunolimab, CAN04) is in phase II clinical studies in pancreatic cancer and non-small cell lung cancer (NCT03267316). As IL-1RAcP is common to all of the abovementioned IL-1 family cytokines, targeting this co-receptor raises the possibility of selective signaling inhibition for different IL-1 family cytokines. Indeed, previous studies of IL-1β and IL-33 signaling complexes have revealed that these cytokines employ distinct mechanisms of IL-1RAcP recruitment even though their overall cytokine/receptor/co-receptor complexes are structurally similar. Here, using functional, biophysical, and structural analyses, we show that antibodies specific for IL-1RAcP can differentially block signaling by IL-1 family cytokines depending on the distinct IL-1RAcP epitopes that they engage. Our results indicate that targeting a shared cytokine receptor is a viable therapeutic strategy for selective cytokine signaling inhibition.
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spelling pubmed-87400702022-01-08 Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor Fields, James K. Kihn, Kyle Birkedal, Gabriel S. Klontz, Erik H. Sjöström, Kjell Günther, Sebastian Beadenkopf, Robert Forsberg, Göran Liberg, David Snyder, Greg A. Deredge, Daniel Sundberg, Eric J. Front Immunol Immunology Interleukin-1 (IL-1) family cytokines are potent mediators of inflammation, acting to coordinate local and systemic immune responses to a wide range of stimuli. Aberrant signaling by IL-1 family cytokine members, however, is linked to myriad inflammatory syndromes, autoimmune conditions and cancers. As such, blocking the inflammatory signals inherent to IL-1 family signaling is an established and expanding therapeutic strategy. While several FDA-approved IL-1 inhibitors exist, including an Fc fusion protein, a neutralizing antibody, and an antagonist cytokine, none specifically targets the co-receptor IL-1 receptor accessory protein (IL-1RAcP). Most IL-1 family cytokines form productive signaling complexes by binding first to their cognate receptors – IL-1RI for IL-1α and IL-1β; ST2 for IL-33; and IL-36R for IL-36α, IL-36β and IL-36γ – after which they recruit the shared secondary receptor IL-1RAcP to form a ternary cytokine/receptor/co-receptor complex. Recently, IL-1RAcP was identified as a biomarker for both AML and CML. IL-1RAcP has also been implicated in tumor progression in solid tumors and an anti-IL1RAP antibody (nadunolimab, CAN04) is in phase II clinical studies in pancreatic cancer and non-small cell lung cancer (NCT03267316). As IL-1RAcP is common to all of the abovementioned IL-1 family cytokines, targeting this co-receptor raises the possibility of selective signaling inhibition for different IL-1 family cytokines. Indeed, previous studies of IL-1β and IL-33 signaling complexes have revealed that these cytokines employ distinct mechanisms of IL-1RAcP recruitment even though their overall cytokine/receptor/co-receptor complexes are structurally similar. Here, using functional, biophysical, and structural analyses, we show that antibodies specific for IL-1RAcP can differentially block signaling by IL-1 family cytokines depending on the distinct IL-1RAcP epitopes that they engage. Our results indicate that targeting a shared cytokine receptor is a viable therapeutic strategy for selective cytokine signaling inhibition. Frontiers Media S.A. 2021-12-24 /pmc/articles/PMC8740070/ /pubmed/35003094 http://dx.doi.org/10.3389/fimmu.2021.779100 Text en Copyright © 2021 Fields, Kihn, Birkedal, Klontz, Sjöström, Günther, Beadenkopf, Forsberg, Liberg, Snyder, Deredge and Sundberg https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Fields, James K.
Kihn, Kyle
Birkedal, Gabriel S.
Klontz, Erik H.
Sjöström, Kjell
Günther, Sebastian
Beadenkopf, Robert
Forsberg, Göran
Liberg, David
Snyder, Greg A.
Deredge, Daniel
Sundberg, Eric J.
Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor
title Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor
title_full Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor
title_fullStr Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor
title_full_unstemmed Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor
title_short Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor
title_sort molecular basis of selective cytokine signaling inhibition by antibodies targeting a shared receptor
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740070/
https://www.ncbi.nlm.nih.gov/pubmed/35003094
http://dx.doi.org/10.3389/fimmu.2021.779100
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