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Molecular basis of selective cytokine signaling inhibition by antibodies targeting a shared receptor

View ORCID ProfileJames K. Fields, Kyle Kihn, View ORCID ProfileGabriel S. Birkedal, View ORCID ProfileErik H. Klontz, View ORCID ProfileKjell Sjöström, View ORCID ProfileSebastian Günther, Robert Beadenkopf, Göran Forsberg, David Liberg, View ORCID ProfileGreg A. Snyder, View ORCID ProfileDaniel Deredge, View ORCID ProfileEric J. Sundberg
doi: https://doi.org/10.1101/2021.05.07.443154
James K. Fields
1Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
2Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
3Program in Molecular Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
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Kyle Kihn
4Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, United States
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Gabriel S. Birkedal
5Cantargia AB, Lund, Sweden
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Erik H. Klontz
1Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
2Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
3Program in Molecular Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
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Kjell Sjöström
5Cantargia AB, Lund, Sweden
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Sebastian Günther
6Deutsches Elektronen-Synchrotron DESY, Hamburg, Germany
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Robert Beadenkopf
1Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
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Göran Forsberg
5Cantargia AB, Lund, Sweden
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David Liberg
5Cantargia AB, Lund, Sweden
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Greg A. Snyder
1Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
2Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
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Daniel Deredge
4Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, United States
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Eric J. Sundberg
7Department of Biochemistry, Emory School of Medicine, Atlanta, GA, United States
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  • For correspondence: eric.sundberg@emory.edu
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Abstract

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 exists, 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.

Competing Interest Statement

Competing Interests Statement: D.L, G.F., K.S., and G.B. are employees of Cantargia AB (Medicon Village, Lund, Sweden). Cantargia AB is the owner of the intellectual property rights for CAN03 and CAN04 for use in the treatment and diagnosis of neoplastic disorders. Cantargia AB partially funded this research. The remaining authors declare no competing financial interests.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 08, 2021.
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Molecular basis of selective cytokine signaling inhibition by antibodies targeting a shared receptor
James K. Fields, Kyle Kihn, Gabriel S. Birkedal, Erik H. Klontz, Kjell Sjöström, Sebastian Günther, Robert Beadenkopf, Göran Forsberg, David Liberg, Greg A. Snyder, Daniel Deredge, Eric J. Sundberg
bioRxiv 2021.05.07.443154; doi: https://doi.org/10.1101/2021.05.07.443154
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Molecular basis of selective cytokine signaling inhibition by antibodies targeting a shared receptor
James K. Fields, Kyle Kihn, Gabriel S. Birkedal, Erik H. Klontz, Kjell Sjöström, Sebastian Günther, Robert Beadenkopf, Göran Forsberg, David Liberg, Greg A. Snyder, Daniel Deredge, Eric J. Sundberg
bioRxiv 2021.05.07.443154; doi: https://doi.org/10.1101/2021.05.07.443154

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