Abstract 7055: An IL1RAP ADC is efficacious in distinct oncofusion-driven pediatric cancers
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".