Abstract 2360: ADV101, a first-in-class IL-1RAP ADC demonstrates significant anti-tumor activity in solid tumor models

Abstract

Abstract Chronic inflammation is intricately linked to cancer development, and the IL-1 cytokine family stands out as pivotal regulators of inflammation. All the pro-inflammatory cytokines within the IL-1 family rely on a single co-receptor called IL-1RAP which therefore emerges as a crucial and central node for modulating these pathways. While healthy tissues, except for the placenta, showed minimal plasma membrane IL-1RAP expression, tumor tissues exhibited high IL-1RAP expression, particularly in Acute myeloid leukaemia, Ewing sarcoma, ovarian cancer, head and neck, and squamous gastric and oesophageal cancers. In addition, elevated IL-1RAP expression in haematological and solid malignancies has also been associated with poor overall survival, making it an attractive target for therapeutic intervention. In this study, we present the development and characterization of an antibody-drug-conjugate (ADC) targeting IL-1RAP for potential anti-tumor applications. Following on from this, an anti-IL-1RAP antibody, ADV58, was generated and confirmed to have the anticipated biophysical, specificity, and functional properties, including low nanomolar affinity (SPR and ELISA), selectivity/specificity to human IL-1RAP, and internalization potential into IL-1RAP-positive tumor cells. In addition, ADV58 bind similarly well to human, cynomolgus and rhesus monkey IL-1RAP antigens but not to rat and mouse. Altogether these properties made ADV58 an ideal candidate for an ADC program. Concurrently, solid tumor cell lines from indications of interest with elevated IL-1RAP expression were identified, laying the groundwork for disease relevant pre-clinical tumor models. Using these models, the anti-tumor potential of ADV101 (ADV58-derived ADC) was assessed in vitro and in vivo in successful proof-of-concept studies by conjugating ADV58 with monomethyl auristatin E (MMAE, DAR of 4) or Deruxtecan (DXd, DAR of 8). Humanisation and conjugation did not compromise binding of the naked antibody, the ADV58-MMAE or the ADV58-DXd ADCs to human and non-human primate IL-1RAP. In vitro, the ADCs selectively killed IL-1RAP-positive tumor cells. In vivo efficacy studies in IL-1RAP-positive subcutaneous xenograft tumor models also demonstrated a significant dose-dependent and IL-1RAP antigen-dependent anti-tumor response for both anti-IL-1RAP ADCs. Altogether the robust preclinical data package supports the continued development of ADV101 as a novel targeted ADC therapeutic strategy for a broad spectrum of cancers. Citation Format: Richard C. A. Sainson, Laura Demolis, Edouard De Dreuzy, Olivier Favre-Bulle, Alexis Collette, Lucas Bourhis, Soha Reda El Sayed, Delphine Genin, Clementine Primus, Lucie Bouquet, Ksenija Pavletic, Christophe Ferrand, Marina Deschamps, Stephane Lameynardie, Erik Rutjens, Jens Hasskarl. ADV101, a first-in-class IL-1RAP ADC demonstrates significant anti-tumor activity in solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2360.