ZW427：一种携带新型pan-RAS抑制剂载荷、靶向Ly6E的抗体药物偶联物，用于治疗RAS突变癌症

Aberrant RAS signaling is implicated as an oncogenic driver in up to 30% of cancers. Mutant selective RAS inhibitors (RASi) have been clinically approved in select indications, but their durable efficacy is hampered by acquired alterations that render tumors refractory to drug. Pan-RASi are showing broad clinical promise, but their full potential has been limited by toxicities likely arising from on-target inhibition of wild-type RAS in normal tissues, as well as by the emergence of resistance. These challenges may be improved upon by optimizing delivery of a RASi via an antibody drug conjugate mechanism. Lymphocyte antigen 6 family member E (Ly6E) is a GPI anchored cell surface protein with minimal presence in normal tissues that is prevalently overexpressed in many solid tumors including those which commonly feature oncogenic RAS mutations, such as NSCLC, PDAC, and CRC. We sought to leverage the ability of an ADC to increase the delivery of a novel pan-RASi payload to tumors for improved response, and to provide a differentiated safety profile that mitigates the toxicity limitations of current small molecule pan-RASi. ZW427 comprises a novel Ly6E-targeted humanized IgG1 antibody conjugated to a novel pan-RAS inhibitor via a cleavable linker. The anti-Ly6E antibody was discovered and optimized for ADC application, with a focus on binding, specificity, internalization and payload delivery to tumor cell lines. To study the therapeutic potential of ZW427, in vitro ADC cytotoxicity was assessed in spheroids derived from a panel of RAS mutated cancer cell lines. Internalization and spheroid penetration were evaluated, and tumor cell co-culture assays were performed to assess bystander-mediated cell killing potential. Anti-tumor activity of ZW427 was investigated in multiple RAS mutated mouse xenograft models with a range of Ly6E-expression. Pharmacodynamic aspects of RAS inhibition were also assessed. ZW427 exhibited target specific binding to cancer cells, highly effective internalization and bystander-mediated killing. Importantly, the ADC demonstrated potent and target-specific cytotoxicity in multiple Ly6E-expressing cancer cell spheroids. A single administration of ZW427 resulted in anti-tumor activity across a range of xenograft models. The pan-RASi ADC platform that has been developed shows encouraging tolerability in mice and an imminent toxicology study of ZW427 in non-human primates will further define its safety profile. Overall, the data supports the potential of ZW427 as a novel, highly differentiated therapeutic agent against Ly6E-expressing RAS mutant cancer indications.