IL1RAP Antibody–Drug Conjugates Potently Target Primary and Metastatic Diseases in Multiple Oncofusion-Driven Cancers

Gene fusions generated by chromosomal rearrangements function as oncogenic drivers in human cancers. We previously showed that EWSR1-ETS oncofusions of Ewing sarcoma directly induce surface expression of IL1 receptor accessory protein (IL1RAP), which along with limited expression in healthy tissues except in the placenta nominate IL1RAP as a promising Ewing sarcoma immunotherapy target. We therefore engineered antibody-drug conjugates (ADC) with different cytotoxic payloads to target IL1RAP. ADCs potently blocked tumor growth and induced durable regression of Ewing sarcoma xenografts in mice and diminished metastatic dissemination in vivo. Moreover, we show that other oncofusions also induce IL1RAP expression in diverse cancers, including NPM-ALK in anaplastic large cell lymphoma and ETV6-NTRK3 in multiple tumor types. IL1RAP expression rendered these malignancies similarly vulnerable to IL1RAP-targeting ADCs, which effectively blocked the growth of ALCL xenografts and syngeneic ETV6-NTRK3+ sarcomas. Lack of detectable normal tissue toxicity, including in nonhuman primates, supports the further clinical translation of IL1RAP-targeting ADCs. SIGNIFICANCE: The IL1RAP surface protein is induced by multiple oncogenic fusions, including EWSR1-ETS, NPM-ALK, and EN in distinct malignancies, rendering these cancers vulnerable to anti-IL1RAP ADCs. We demonstrate that IL1RAP-targeting ADCs have potent efficacy in both primary and metastatic diseases and are well tolerated in nonhuman primates, warranting their further clinical translation.