XNW27011的临床前研发：一种靶向claudin18.2的抗体偶联药物，用于治疗CLDN18.2阳性实体瘤

Claudin (CLDN) 18.2, a member of a large family of transmembrane proteins with distinct functions, is highly expressed in cancers including gastric and pancreatic adenocarcinomas. Unlike in normal tissue, CLDN18.2 is exposed on epithelial surfaces in malignancy. It is suggested that CLDN18.2 is an ideal target for cancer therapy. So far, drug targeting CLDN18.2 has been approved for treating gastric cancer. XNW27011, an antibody-drug conjugate (ADC) composed of a monoclonal antibody (mAb) targeting CLDN18.2 with a toxin (payload, YL0010014) site-specifically conjugated via a cleavable linker with a drug-antibody ratio (DAR) of 8. XNW27011 is under development by Evopoint Biosciences for the treatment of patients with various CLDN 18.2-positive solid tumors including gastric cancers and pancreatic cancers in China. Here we present the preclinical development of a novel therapeutic CLDN18.2 ADC. In preclinical pharmacology studies, XNW27011 specifically binds to cells expressing human CLDN18.2 with high affinity but not to the closely related Claudin 18.1. XNW27011 demonstrated potent antiproliferative activity with CLDN 18.2 highly-expressed cell lines including arresting the cell cycle at the G2/M stage and inducing apoptosis in a variety of in vitro pharmacology studies. XNW27011 also exhibited similar activities to the naked antibody (XNW27011-mAb), including antibody-dependent cell-mediated cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), internalization activities, and bystander effect. XNW27011 as a single agent displayed potent antitumor activities in multiple in vivo xenograft models of human gastric and pancreatic cancer, including PDX models (PDX001 [gastric cancer] and PDX002 [pancreatic cancer]) and CDX models (NUGC-4 and NUGC-4 CLDN 18.2) with low or high CLDN18.2 expression., XNW27011 achieved partial tumor regression (PR) and complete tumor regression (CR) in most mouse xenograft models at well tolerated iv doses (3 or 10 mg/kg). In nonclinical pharmacokinetics of XNW27011 in SD rats and Cynomolgus monkeys by intravenous infusion, XNW27011 showed good ADME characteristics in that it was stable in the bloodstream and exposure to the payload is very low. In toxicity studies, XNW27011 displays good tolerability with wide therapeutic windows in both SD rats and Cynomolgus monkeys. It is particularly important to note that XNW27011 has no toxic effects on the lungs in both rats and monkeys. In summary, XNW27011 has demonstrated potent in vitro and in vivo antitumor effects, favorable pharmacokinetic and an acceptable safety margin. XNW27011 is expected to be a potent therapeutic ADC candidate in cancer treatment of CLDN 18.2-positive solid tumors including gastric and pancreatic adenocarcinomas. Clinical activity of XNW27011 is currently under evaluation in a Phase III clinical trial (CTR20252730).