Antibodies targeting the shared cytokine receptor IL-1 receptor accessory protein invoke distinct mechanisms to block all cytokine signaling

• Published in: Cell reports (Cambridge) Vol. 43; no. 5; p. 114099
• Main Authors: Fields, James K., Gyllenbäck, Elin Jaensson, Bogacz, Marek, Obi, Juliet, Birkedal, Gabriel Svensson, Sjöström, Kjell, Maravillas, Kino, Grönberg, Caitríona, Rattik, Sara, Kihn, Kyle, Flowers, Maria, Smith, Ally K., Hansen, Nils, Fioretos, Thoas, Huyhn, Chau, Liberg, David, Deredge, Daniel, Sundberg, Eric J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28-05-2024
• Subjects: 3G5; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; antibody; Basic Medicine; CAN10; CP: Immunology; cytokine; Cytokines - metabolism; Humans; IL-1; IL-33; IL-36; Immunologi inom det medicinska området; Immunology in the medical area; Inflammation - immunology; Inflammation - metabolism; Interleukin-1 Receptor Accessory Protein - metabolism; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; shared receptor; Signal Transduction; signaling inhibition; cytokine; signaling inhibition; CP: Immunology; CAN10; 3G5; antibody; shared receptor; IL-1; IL-36; IL-33
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114099

Interleukin-1 (IL-1)-family cytokines are potent modulators of inflammation, coordinating a vast array of immunological responses across innate and adaptive immune systems. Dysregulated IL-1-family cytokine signaling, however, is involved in a multitude of adverse health effects, such as chronic inflammatory conditions, autoimmune diseases, and cancer. Within the IL-1 family of cytokines, six—IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ—require the IL-1 receptor accessory protein (IL-1RAcP) as their shared co-receptor. Common features of cytokine signaling include redundancy of signaling pathways, sharing of cytokines and receptors, pleiotropy of the cytokines themselves, and multifaceted immune responses. Accordingly, targeting multiple cytokines simultaneously is an emerging therapeutic strategy and can provide advantages over targeting a single cytokine pathway. Here, we show that two monoclonal antibodies, CAN10 and 3G5, which target IL-1RAcP for broad blockade of all associated cytokines, do so through distinct mechanisms and provide therapeutic opportunities for the treatment of inflammatory diseases.
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•Two mAbs specific for IL-1RAcP block all IL-1, IL-33, and IL-36 signaling•CAN10 and 3G5 block signaling with similar potency but through distinct mechanisms•Blocking all IL-1RAcP cytokines is better than solely IL-1 in a mouse model•Shared receptors are viable therapeutic targets; CAN10 is in clinical trials
Fields et al. demonstrate the viability of targeting a shared cytokine receptor for comprehensive signaling blockade of all associated cytokines. CAN10 and 3G5, two anti-IL-1RAcP antibodies, target distinct epitopes on this shared receptor and potently block IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ signaling.