Anti-IL1RAP Antibodies for Pan-Inhibition of IL-1 Family Cytokine Signaling in Inflammatory Diseases and Oncology

Abstract The interleukin-1 (IL-1) superfamily of cytokines—comprising the IL-1, IL-33, and IL-36 subfamilies—orchestrates a vast array of innate and adaptive immune responses. While physiological activation of these pathways is essential for host defense and tissue repair, their chronic dysregulation is pathognomonic of a broad spectrum of autoimmune diseases and malignancies. Current therapeutic modalities largely rely on the neutralization of single cytokines, an approach often limited by the functional redundancy and compensatory signaling loops inherent to the IL-1 superfamily. The Interleukin-1 Receptor Accessory Protein (IL1RAP) serves as an obligatory co-receptor for IL-1, IL-33, and IL-36 subfamilies, functioning as a molecular bottleneck for pro-inflammatory signaling. Herein, we report the development and comprehensive characterization of two humanized monoclonal antibodies, DXP-006 and DXP-106, which target a unique epitope on domain 2 of IL1RAP. Cryo-electron microscopy studies at 3.55 Å resolution reveal that these antibodies lock the critical c2d2 loop of IL1RAP, sterically occluding its recruitment to IL-1R1, ST2 and IL-36R binary complexes and potently blockade IL-1, IL33, and IL-36 signaling. DXP-006, engineered with a half-life-extended and effector-silenced Fc, exerts profound efficacy in murine models of psoriasis, superior to the clinical benchmark bimekizumab. Conversely, DXP-106, engineered with a defucosylated Fc to enhance antibody-dependent cellular cytotoxicity, exhibits potent antitumor activity in non-small cell lung cancer xenografts. These findings position DXP-006 and DXP-106 as ideal therapeutics for IL-1 family-driven autoimmunity and IL1RAP-positive cancers. One Sentence Summary Anti-IL1RAP antibodies block multiple IL-1 family cytokines simultaneously, showing superior efficacy in inflammation and cancer models.