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Blockade of IL-1α and IL-1β signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy

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Abstract

IL-1α and IL-1β are both involved in several aspects of tumor biology, including tumor initiation, progression, metastasis, and not least in resistance to various therapies. IL-1α can function as an alarmin to signal cellular stress, and acts to induce downstream events, including production of IL-1β, to amplify the signal. Both IL-1α and IL-1β act through the same receptor complex, IL-1R1-IL1RAP, to mediate signal transduction. IL1RAP is expressed on tumor cells and in the tumor microenvironment by for example CAF, macrophages and endothelial cells. The anti-IL1RAP antibody nadunolimab (CAN04) inhibits both IL-1α and IL-1β signaling and induces ADCC of IL1RAP-expressing tumor cells. As both IL-1α and IL-1β mediate chemoresistance, the aim of this study was to explore the potential synergy between nadunolimab and chemotherapy. This was performed using the NSCLC PDX model LU2503 and the syngeneic MC38 model, in addition to in vitro cell line experiments. We show that chemotherapy induces expression and release of IL-1α from tumor cells and production of IL-1β-converting enzyme, ICE, in the tumor stroma. IL-1α is also demonstrated to act on stromal cells to further induce the secretion of IL-1β, an effect disrupted by nadunolimab. Nadunolimab, and its surrogate antibody, synergize with platinum-based as well as non-platinum-based chemotherapy to induce potent anti-tumor effects, while blockade of only IL-1β signaling by anti-IL-1β antibody does not achieve this effect. In conclusion, blockade of IL1RAP with nadunolimab reduces IL-1-induced chemoresistance of tumors.

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Funding

This work was funded in whole by Cantargia AB.

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Authors and Affiliations

  1. Cantargia AB, Ideon Gateway, Scheelevägen 27, 22363, Lund, Sweden

    Camilla Rydberg Millrud, Adnan Deronic, Caitríona Grönberg, Elin Jaensson Gyllenbäck, Göran Forsberg & David Liberg

  2. Truly Labs AB, Medicon Village, 22381, Lund, Sweden

    Karin von Wachenfeldt

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Contributions

Conceptualization: CRM, KVW, GF, DL. Methodology: CRM, CG, EJG, KVW, DL. Formal analysis and investigation: CRM, CG. Writing—original draft preparation: AD, CRM. Writing—review and editing: AD, CRM, DL, GF. Supervision: GF, DL.

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Correspondence to David Liberg.

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All authors are current employees of, and/or hold stocks or stock options in, Cantargia AB.

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All animal studies were conducted according to the countries’ legislation following an approved Institutional Animal Care and Use Committee protocol or ethical permit. The care and use of animals was conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care.

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Rydberg Millrud, C., Deronic, A., Grönberg, C. et al. Blockade of IL-1α and IL-1β signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy. Cancer Immunol Immunother 72, 667–678 (2023). https://doi.org/10.1007/s00262-022-03277-3

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