Abstract 4253: Turning pro-tumor inflammation into target opportunity: Development of an IL1RAP ADC for solid tumor treatment

Abstract Chronic and dysregulated inflammation caused by activation of interleukin-1 (IL-1) signaling supports tumor growth and helps establish an immunosuppressive microenvironment. Interleukin 1 receptor accessory protein (IL1RAP, IL-1RAcP, IL1R3) serves as a co-receptor for interleukin 1 receptor type 1 (IL1R1) at the cell membrane and plays a key role in mediating IL-1 signaling. By combining multi-omics and immunohistochemistry analysis, we identified the upregulation of IL1RAP on many solid tumor indications, including melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and esophageal cancer, while normal tissue expression is mainly restricted to the bone marrow. This expression pattern and tumor-supporting biological function makes IL1RAP an attractive target for an antibody-drug conjugate (ADC) therapy approach. Through a hybridoma antibody campaign, we generated a pool of candidate anti-IL1RAP monoclonal antibodies (mAbs) to evaluate as ADC candidates. The candidates all exhibited ability to disrupt the IL-1 signaling cascade but demonstrated variable potency to do so. All of the clones had similar ability to drive drug delivery and direct cytotoxicity to tumor cells as ADCs. These in vitro activities translated into strong in vivo anti-tumor activity in several CDX and PDX human tumor models, with clonal separation only apparent in low expressing models. While strong activity was seen in all CDX models with various IL1RAP expression levels, primary human sample PDX models demonstrated a much stronger expression:response correlation. To evaluate any potential normal tissue liabilities of an IL1RAP ADC, and assess how clone selection may impact this, a primary human bone marrow colony formation unit assay was employed. While several of the anti-IL1RAP antibodies demonstrated on-target myeloid progenitor cell lethality, not all clones were equipotent, despite all driving similar in vivo anti-tumor activity. Collectively this data demonstrates the potential to leverage IL1RAP as an effective and well tolerated ADC and how appropriate antibody selection could potentially aid in increasing the therapeutic index. Citation Format: Yufei Chen, Marlena Gray, Piper Meigs Treuting, Craig Miller, Sara Carbonetti, Katie Snead, Kaleb Smith, Robert Lawrence, Alyson J. Smith. Turning pro-tumor inflammation into target opportunity: Development of an IL1RAP ADC for solid tumor treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4253.