A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models

American Journal of Cancer Research

Yiran Tao¹  Liangze Tang²  Yu Liu³  Yuqin Yao⁴  Qinhuai Lai⁵  Ying Lu⁶  Ruixue Wang⁷ 

[1] Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China;Guangdong Zhongsheng Pharmaceutical Co., Ltd., China;Institute of Digestive Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China;Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China;Research Center for Public Health and Preventive Medicine, West China School of Public Health and Healthy Food Evaluation Research Center, NO. 4 West China Teaching Hospital, Sichuan University, Chengdu, China;School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China;State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China

关键词: 5T4;    gastrointestinal cancer;    antibody-drug conjugate;    DM4;    targeted therapy;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

5T4, also named as trophoblast glycoprotein, is often upregulated in some cancer cells. Here, we demonstrated that 5T4 was highly expressed in gastric, colorectal, and pancreatic cancer, associated with significantly poor prognosis of gastrointestinal (GI) cancer patients. To search for new targeting drugs for GI cancer, we developed a novel anti-5T4 monoclonal antibody with high affinity and robust internalization ability and conjugated it to the potent microtubule inhibitor DM4 to produce conjugate H6-DM4. This antibody-drug conjugate (ADC) displayed significant cytotoxicity in a panel of GI cancer cell lines with IC50 values in the nanomolar range. H6-DM4 eradicated established GI tumor xenograft models at 2.5 mg/kg or 10 mg/kg without observable toxicity. Further, 5T4 was highly expressed in cancer-initiating cells (CICs) compared with non-CICs in colorectal cancer. In vitro and in vivo, treatment with H6-DM4 exhibited a powerful efficacy on colorectal CICs. Additionally, colorectal cancer cells resistant to platinum were effectively eliminated by H6-DM4. Taken together, our results showed 5T4-positive GI cancer cells, colorectal cancer-initiating cells, and platinum-resistant colorectal cancer cells were potently eliminated by H6-DM4, indicating H6-DM4 may be a potential candidate drug for GI cancer treatment.

【 授权许可】

CC BY-NC