Abstract 7055: An IL1RAP ADC is efficacious in distinct oncofusion-driven pediatric cancers

Abstract Our recent studies identified the cell surface protein IL-1 receptor accessory protein (IL1RAP) as a crucial regulator of redox homeostasis and a suppressor of ferroptosis (iron-mediated cell death) in Ewing sarcoma (EwS). IL1RAP directly binds to the CD98/xCT plasma membrane antiporter to enhance cystine uptake, thereby replenishing cysteine and glutathione (GSH) pools in EwS cells. Moreover, when extracellular cystine is limited, IL1RAP induces cystathionine gamma lyase (CTH) to activate the transsulfuration (TSS) pathway for de novo cysteine synthesis. IL1RAP depletion diminishes GSH pools and induces oxidative stress to trigger anoikis and ferroptosis, thereby inhibiting EwS metastatic capacity. Importantly, IL1RAP is minimally expressed in normal tissues, including blood and bone marrow, with placenta as the only normal tissue to express IL1RAP, nominating this protein as a promising immunotherapy target. Here, we uncover that distinct fusion oncoproteins activate IL1RAP expression in cancers of different lineages, including EWS-ETS fusions in Ewing sarcoma (EwS), the ETV6-NTRK3 fusion in diverse tumor types, and the NPM-ALK fusion in anaplastic large cell lymphoma (ALCL). To target IL1RAP in these cancers via immunotherapy, we identified a highly specific IL1RAP binder from phage-display biopanning, and engineered an IL1RAP-directed human IgG based antibody-drug conjugate (ADC; X12-IL1RAP-PBD) linked to the DNA damaging agent, pyrrolobenzodiazepine (PBD). In proof-of-concept studies, our proprietary X12-IL1RAP-PBD induced potent DNA damage, apoptosis, and bystander cell killing in in vitro. In preclinical mouse models, X12-IL1RAP-PBD induces dramatic and durable regression of tumor xenografts expressing of the oncofusions at dosing of only 0.2mg/kg. Moreover, essentially no signs of toxicity were noted, with stable body weights and no histological evidence of toxicity in vital organs such as liver, lung, kidney, and brain. Moreover, X12-IL1RAP-PBD fully blocked tail vein injected EwS cell-induced liver changes in vivo, again without any toxicity. Thus, this first-in-class IL1RAP-targeting ADC is highly efficacious in preclinical models of multiple oncofusion-driven cancers, warranting further clinical translation. Citation Format: Haifeng Zhang, Wei Li, Xiaqiu Yang, Qingfeng Huang, Yue Zhou Huang, Alberto Delaidelli, Andrew Lytle, Melanie Rouleau, Christian Steidl, Dimiter Dimitrov, Poul Sorensen. An IL1RAP ADC is efficacious in distinct oncofusion-driven pediatric cancers [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 7055.