ZW439，一种新型靶向CLDN18.2的pan-RAS抑制剂抗体偶联药物，用于治疗RAS突变胰腺癌

Pancreatic cancer remains one of the most difficult to treat cancers, with 5-year survival rates of just 13%, and there is an urgent unmet need for novel, differentiated, and effective therapeutics. Recently, encouraging progress has been made through inhibition of RAS, a key oncogenic driver mutated in over 90% of pancreatic ductal adenocarcinoma (PDAC). Antibody drug conjugates (ADCs) have demonstrated clinical success at improving the effectiveness of multiple respective classes of small molecules. The full therapeutic potential of pan-RAS inhibitors (pan-RASi) 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 enhancing delivery of a RASi via an antibody drug conjugate mechanism. Here, we seek to leverage the ability of ADCs to enhance 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. To this end, the novel pan-RASi ADC ZW439 is directed to CLDN18.2, a clinically validated oncology target that is highly expressed in PDAC. A novel potent pan-RAS inhibitor ADC platform was developed through synthesis, screening, and iterative optimisation of payloads and drug-linkers for favorable ADC biophysical properties, antitumor activity, tolerability and pharmacokinetics (PK). A novel CLDN18.2 targeted antibody was selected for optimal ADC properties including its binding and internalization to CLDN18.2 expressing cells. Tumor cell spheroids were utilized to determine the cytotoxicity of the pan-RASi ADC, and its bystander activity was determined in CLDN18.2 positive and negative tumor cell co-cultures. The antitumor activity and PK of ZW439 were evaluated in multiple mouse xenograft models. The novel humanized IgG1 antibody of ZW439 features strong and exclusive binding to CLDN18.2 and demonstrates superior internalization to CLDN18.2 expressing tumor cells compared to a clinical benchmark CLDN18.2 targeted antibody. ZW439 demonstrates potent target-specific cytotoxicity to RAS-mutated tumor cells expressing a range of CLDN18.2 levels and drives effective bystander activity to antigen negative cells. In vivo, ZW439 demonstrates highly efficacious anti-tumor activity in multiple CLDN18.2 expressing xenografts and has a favourable PK profile. ZW439's pan-RASi ADC drug-linker platform demonstrates encouraging tolerability, with no significant toxicity observed following dosing up to 200 mg/kg in mice. The encouraging preclinical profile of ZW439 supports its potential as a differentiated therapeutic for the treatment of Pancreatic cancer.