Abstract 1642: A pan-RASi antibody-drug conjugate platform with high activity in RAS-mutant cancers

Abstract Aberrant activation of RAS protein by oncogenic mutation is a critical driver of tumorigenesis, yet effective and tolerable inhibition of RAS signaling remains a major unmet need. Tricomplex RAS inhibitors (RASi) are an emerging class of drugs that disrupt RAS signaling by forming a ternary complex with cyclophilin A (CypA) and the active, GTP-bound conformation of RAS [RAS(ON)], thereby blocking downstream signaling through the MAPK and PI3K pathways. RMC-6236 is an orally administered, potent pan-RAS inhibitor and is a prototypical drug in this class. Despite promising initial results in the clinic, treatment-related adverse events such as skin and gastrointestinal toxicities have emerged, likely as a result of on-target, off-tumor inhibition of RAS in normal tissues. We hypothesized that targeted delivery of a potent pan-RASi as an antibody-drug conjugate (ADC) payload could enhance anti-tumor efficacy and improve tolerability, thereby overcoming the limitations of orally administered RASi small molecules. Here we report the generation of a novel antibody-drug conjugate platform designed for the treatment of RAS-mutant cancers. To identify suitable ADC payloads, novel pan-RAS inhibitors were synthesized with a focus on high potency, favorable polarity, and suitable functionality for linker attachment. A library of over 100 novel linkable pan-RAS inhibitors was synthesized and screened, with multiple candidates demonstrating significantly higher potency than RMC-6236 across a panel of KRAS-mutant cell lines. Mechanistic characterization of RAS binding was achieved via surface plasmon resonance, demonstrating formation of the binary (CypA:inhibitor) and ternary (RAS:CypA:inhibitor) complexes. Disruption of RAS–RAF interaction was profiled using homogeneous time resolved fluorescence. Drug-linkers were generated from selected payloads and used to produce ADCs with a drug-to-antibody ratio of 8. Linker format and payload attachment site were tuned to improve drug-linker hydrophilicity and ADC pharmacokinetic characteristics. Pan-RASi ADCs were profiled for targeted antitumor activity in tumor cell lines. More than 20 ADCs with distinct drug-linkers were evaluated and >10 were selected for evaluation in cell line derived xenograft models. Strong regressions were observed with single doses as low as 1 mg/kg in multiple models. Evaluation in mice demonstrated no significant toxicity at doses up to 200 mg/kg. Safety was further assessed in non-human primate studies. Collectively, the promising antitumor activity and manageable tolerability profile support the application of this novel pan-RASi ADC platform to clinically meaningful targets across NSCLC, PDAC, and CRC. Citation Format: Graham A. Garnett, Victoria K. Harman-McKenna, Taixiang Wang, Jodi Wong, Truman Hirkala-Schaefer, Michael G. Brant, Mark E. Petersen, Catalina Suarez, Khushi Lodaya, Rehan Higgins, Jesse H. Leblanc, Linglan Fu, Cathy Fu, Sara Weeres, Manuel Lasalle, Kaylee J. Wu, Vidhi Khanna, Sam Lawn, Kurt Stahl, Vincent Fung, Raffaele Colombo, Stuart D. Barnscher, Jamie R. Rich, . A pan-RASi antibody-drug conjugate platform with high activity in RAS-mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1642.