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A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models.
Wang R1,2, Lai Q1, Tang L1, Tao Y1, Yao Y1,3,2, Liu Y1, Lu Y1, Shen C4, Lu R5, Fan C6, Zhang R1, Wang Y1, Yu L1, Yang T1,4, Wu Y1, Peng Y1, Wei X1,2,7, Fu Y1, Lai W1, Gou L1, Yang J1,2.
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Abstract
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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934552/

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