Abstract 6737: RAS inhibitors as payloads of ADCs to treat RAS-mutant tumors

Abstract Background: Ras mutation has been identified as one of the major oncogenes in many cancers. Recent breakthroughs in regulating the activity of RAS proteins have led to the discovery of several clinical therapeutic molecules, such as Sotorasib and Adagrasib. However, for patients with RAS mutations, drugs with broader indications, higher potency, better tolerability, and longer efficacy are urgently needed. On the other hand, ADC, as a new precise and efficient drug delivery method, provides a potential solution to the above unmet needs. Here, we disclose a new class of ADCs whose payloads target RAS variant proteins and exhibit excellent antitumor effects and tolerability both in vitro and in vivo. Method: Both selective and pan-RAS inhibitors were conjugated to various antibodies via cleavable peptide linkers and ancillary groups to improve druggability. The primary biological activities of payloads and ADCs were examined in a series of cellular proliferation assays. The in vivo antitumor effects of the ADCs were evaluated on selected cell-derived xenograft (CDX) mice models, where body weight changes of the test animals were used to estimate the tolerability of the molecules. Both in vitro and in vivo PK properties of the ADCs were also studied. Results: The potent KRAS G12D selective inhibitor P1 or pan-RAS inhibitor P2 (KRAS-G12C, G12D, G12S, G12V, G13D, etc.) was successfully conjugated with antibodies such as anti-Her2, Trop2, Claudin18.2, etc., with a maximum DAR value of 8. By optimizing the linker and ancillary group, ADC-1 maintained the high potency of its payload P1 in the antigen-specific cancer cell line GP2D (IC50 for P1: 0.5 nM vs ADC-1: 0.4 nM). ADC-1 exhibited excellent anti-tumor effects in animal models. For example, in the GP2D CDX model, a single dose at 10 mpk intravenous injection, 104% TGI (tumor growth inhibition) was observed on day 21. In addition, there was no significant difference in the weight change of the test animals in the ADC treatment group compared with the vehicle group. In both mouse and human plasma, the release of payload P1 from ADC-1 was less than 2% for up to 72 hours. Considering the drug load of approximately 3%wt on ADC, no payload-related safety issues emerged in the study. Conclusion: ADC containing RAS inhibitor is a new approach to treat RAS mutant tumors. It has shown good selectivity and potency in both in vitro and in vivo studies on a variety of tumors. It exhibits good PK and physicochemical properties. It also shows an acceptable safety profile. It is a promising measure for treating patients with RAS mutations in the clinic. Citation Format: Boyu Zhong, Tony Zhang, Zuyong Deng, Guangming Chen, Chunlan Dong, Liangbao Lai, Erchang Shang. RAS inhibitors as payloads of ADCs to treat RAS-mutant tumors [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 6737.