一种在RAS突变型癌症中具有高活性的泛RASi抗体-药物偶联物平台

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.