Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate
Fan-En Kong, Guangmeng Li, Yun-Qiang Tang, Shaoyan Xi, Jane Ho Chun Loong, Meimei Li, Haolong Li, Wei Cheng, Wenjie Zhu, Jia-Qiang Mo, Yuanfeng Gong, Hui Tang, Yue Zhao, Yan Zhang, Stephanie Ma, Xin‐Yuan Guan, Ning‐Fang Ma, Maobin Xie, Ming Liu
Abstract
was highly expressed in embryonic stem cells but markedly decreased in normal tissues. Reactivation of CLDN6 was frequently observed in HCC tumor tissues as well as in premalignant lesions. Functional assays indicated that CLDN6 is not only a tumor-associated antigen but also conferred strong oncogenic effects in HCC. Overexpression of CLDN6 induced phenotypic shift of HCC cells from hepatic lineage to biliary lineage, which was more refractory to sorafenib treatment. The enhanced tumor lineage plasticity and cellular identity change were potentially induced by the CLDN6/TJP2 (tight junction protein 2)/YAP1 (Yes-associated protein 1) interacting axis and further activation of the Hippo signaling pathway. A de novo anti-CLDN6 monoclonal antibody conjugated with cytotoxic agent (Mertansine) DM1 (CLDN6-DM1) was developed. Preclinical data on both HCC cell lines and primary tumors showed the potent antitumor efficiency of CLDN6-DM1 as a single agent or in combination with sorafenib in HCC treatment.