Abstract 1203: ZL-1211 exhibits broad anti-tumor activity in CLDN18.2 high- and low-expressing models

Abstract

Abstract Targeting the lineage marker CLDN18.2 with ADCC-eliciting monoclonal antibody therapeutics has shown promising clinical activity in the gastric, esophageal, and pancreatic cancer indications. However, clinical efficacy was mainly observed in tumors that expressed very high levels of CLDN18.2, which represented only ~30% of cases, and was much less pronounced in tumors with low levels of CLDN18.2. Here we present ZL-1211, a novel CLDN18.2-targeting monoclonal antibody that was engineered to promote enhanced ADCC and to drive efficacy in tumors that exhibit a broad range of CLDN18.2 expression levels. We demonstrate that ZL-1211 can robustly inhibit the growth of tumor cells that express not only high but also low levels of CLDN18.2 in vitro as well as a variety of in vivo models. ZL-1211 strongly induced ADCC, ADCP, and CDC and inhibited the growth of a series of in vitro models more potently than the leading clinical benchmark, including cell lines engineered to exogenously express varying levels of CLDN18.2 as well as gastric and pancreatic cancer cell lines that endogenously express low, medium, and high target levels. Consistent with our in vitro findings, ZL-1211 also exhibited greater anti-tumor efficacy than the leading clinical benchmark in CLDN18.2-positive patient-derived xenograft and syngeneic models in vivo. Together, our data suggest that ZL-1211 might provide therapeutic benefit for a wider spectrum of low- and high-CLDN18.2 expressing tumors than the leading clinical benchmark. A Ph1 dose escalation study to assess the safety and preliminary efficacy of ZL-1211 is planned. Citation Format: Hiroyasu Konno, Yong Li, Xinchuan Dai, Bee Sun, Wenhua Shi, Min Chen, Wenying Li, Shou Li, Lishan Kang, Holly Li, Frank Tao, Sophia Yin, Bingbing Wang, Lishen Shan, Bing Wan, Petter Veiby, James Yan, Karl Hsu, David Bellovin, Omar Kabbarah. ZL-1211 exhibits broad anti-tumor activity in CLDN18.2 high- and low-expressing models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1203.