Abstract 4260: ADV-101: a novel ADC targeting IL-1RAP, leveraging tumor cell and the tumor microenvironment vulnerabilities for enhanced anti-tumor efficacy

Abstract IL-1RAP is the common co-receptor of all IL-1-related cytokines, and constitutes a novel type of ADC target due to its strong expression on both tumor cells and immunosuppressive cells within the tumor microenvironment (TME). The increased value of this target is complemented by the dependency of certain tumors on IL-1RAP-dependent signaling arguing for a lower chance of antigen loss in response to anti-IL-1RAP therapies. IL-1RAP overall low expression in healthy tissues, also minimizes the risk of on-target off-tumor effects. While healthy tissues exhibit minimal plasma membrane IL-1RAP expression, tumoral tissues demonstrate high IL-1RAP expression, particularly in cancers with squamous histology such as HNSCC and ESCC, as well as other tumor types such as GBM, PDAC, Ewing Sarcoma (EWS) and AML.We developed ADV-101, an ADC consisting of a humanized anti-IL-1RAP IgG1 mAb conjugated to a clinically validated topoisomerase I inhibitor via a cleavable linker (DAR of 8). The anti-IL-1RAP antibody of ADV-101 was shown to be highly specific and selective to IL-1RAP, binding to both human and cynomolgus recombinant protein with EC50 values of 0.095 nM and 0.072 nM, respectively (ELISA), and with an EC50 of 6.47 nM to human IL-1RAP (by SPR). The antibody was also demonstrated to bind IL-1RAP-expressing cells from different cancer indications, with EC50 values ranging from 0.35 to 2.1 nM, and showed specific internalization in a panel of IL-1RAP-expressing cell lines, with EC50 values ranging between 0.34 and 4.44 nM. Notably, this binding and internalization were unaffected by the presence of excess IL-1β ligand. There was no impact of payload-linker conjugation on the ADC binding affinity to IL-1RAP protein and expressing cells. The ADC effectively killed IL-1RAP-positive cells in vitro, with IC50 values ranging from 0.02 to 78.5 nM. In vivo, ADV-101 demonstrated strong anti-tumor efficacy in established tumors derived from CDX models (including large tumors) and PDX models. An in vivo efficacy study in six EWS PDX models with varying levels of IL-1RAP expression and derived from both metastatic and primary disease demonstrated high anti-tumor efficacy in 5 out of 6 models, including full tumor regression, even in tumors known to be resistant to topoisomerase I/II inhibitors. ADV-101 safety was further established in a non-human primate (NHP) dose-range finding toxicity study, showing no severe adverse events up to the highest dose tested (50 mg/kg), together with robust pharmacokinetics data confirming exposure. Altogether, these findings warrant further development to bring ADV-101 to the clinic. Citation Format: Edouard De Dreuzy, Soha El Sayed, Lucie Bouquet, Stephane Lameynardie, Delphine Genin, Amandine Barberot, Lucas Bourhis, Lucas Demontrond, Clementine Primus, Christophe Ferrand, Marina Deschamps, Alexis Delabriére, Laura Demolis, Erik Rutjens, Jens Hasskarl, Ksenija Pavletic, Richard Charles Alfred Sainson. ADV-101: a novel ADC targeting IL-1RAP, leveraging tumor cell and the tumor microenvironment vulnerabilities for enhanced anti-tumor efficacy [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 4260.