IL1RAP antibody-drug conjugates potently target primary and metastatic disease 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 (EwS) directly induce surface expression of IL1 receptor accessory protein (IL1RAP), which along with limited expression in healthy tissues except placenta nominate IL1RAP as a promising EwS immunotherapy target. We therefore engineered antibody-drug conjugates (ADCs) with different cytotoxic payloads to target IL1RAP. ADCs potently blocked tumor growth and induced durable regression of EwS 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 (ALCL), and ETV6-NTRK3 in multiple tumor types. IL1RAP expression rendered these malignancies similarly vulnerable to IL1RAP-targeting ADCs, which effectively blocked growth of ALCL xenografts and syngeneic ETV6-NTRK3+ sarcomas. Lack of detectable normal tissue toxicity, including in non-human primates, support the further clinical translation of IL1RAP-targeting ADCs.

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Publication Details

Journal
Cancer Discovery
Published
2026-04-13
DOI
https://doi.org/10.1158/2159-8290.cd-25-1036
Primary Topic
HER2/EGFR in Cancer Research
Type
article
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article

IL1RAP antibody-drug conjugates potently target primary and metastatic disease in multiple oncofusion-driven cancers

Andrew Lytle, John M. Maris, Xiaqiu Yang, Yue Z. Huang et al.
Cancer Discovery
HER2/EGFR in Cancer Research
article

IL1RAP antibody-drug conjugates potently target primary and metastatic disease in multiple oncofusion-driven cancers

Andrew Lytle, John M. Maris, Xiaqiu Yang, Yue Z. Huang, Virginia Adamiak, Roland Imle, Kerry J. Savage, Kristopher R. Bosse, E Li, Qiaochu Lin, Michael M. Lizardo, Alberto Delaidelli, Christian Steidl, Soha Reda El Sayed, Edouard De Dreuzy, Ana Banito, Graham W. Slack, Rieko Ishima, Lucie Bouquet, Delphine Genin, Richard C.A. Sainson, Raymond Lai, Junjie Yang, Mélanie Rouleau, Poul H. Sorensen, Dimiter S. Dimitrov, Laura Demolis, Wei Li, Qingfeng Huang, Lucas Bourhis, Seungmin Shin, Amandine Barberot, Lucas Demontrond, Haiqing Hua, Aarzoo Arzoo, Shreya Sanadi, Stephane Lameynardie, Clémentine Primus, Alexis Delabrière
article en

Abstract

Gene fusions generated by chromosomal rearrangements function as oncogenic drivers in human cancers. We previously showed that EWSR1-ETS oncofusions of Ewing sarcoma (EwS) directly induce surface expression of IL1 receptor accessory protein (IL1RAP), which along with limited expression in healthy tissues except placenta nominate IL1RAP as a promising EwS immunotherapy target. We therefore engineered antibody-drug conjugates (ADCs) with different cytotoxic payloads to target IL1RAP. ADCs potently blocked tumor growth and induced durable regression of EwS 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 (ALCL), and ETV6-NTRK3 in multiple tumor types. IL1RAP expression rendered these malignancies similarly vulnerable to IL1RAP-targeting ADCs, which effectively blocked growth of ALCL xenografts and syngeneic ETV6-NTRK3+ sarcomas. Lack of detectable normal tissue toxicity, including in non-human primates, support the further clinical translation of IL1RAP-targeting ADCs.

Cancer Discovery
BC Cancer Agency (CA), Children's Hospital of Philadelphia (US), University of Alberta (CA), Inserm (FR), University of Pittsburgh (US), German Cancer Research Center (DE), Heidelberg University (DE), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), CEA Grenoble (FR), Shantou University (CN), Shantou University Medical College (CN), BC Cancer Foundation (CA), University of Pittsburgh Medical Center (US), Io Therapeutics (United States) (US), Canadian Centre for Applied Research in Cancer Control (CA), Cell Biologics (United States) (US), École Nationale Supérieure des Mines de Paris (FR), Université Grenoble Alpes (FR)
Openalex Percentile: Top 18%
HER2/EGFR in Cancer Research
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