Hang Zhang, Yuxi Wang, Yangping Wu, Xiaohua Jiang, Yiran Tao, Yuqin Yao, Yujia Peng, Xiangzheng Chen, Yuyin Fu, Lin Yu, Ruixue Wang, Qinhuai Lai, Weirong Lai, Wenting Li, Yuhuan Kang, Shuli Yi, Ying Lu, Lantu Gou, Min Wu and Jinliang Yang

Signal Transduction and Targeted Therapy 2, Article number: 17015 (2017)  doi:10.1038/sigtrans.2017.15

Abstract:

Antibody–drug conjugates (ADCs) take the advantage of monoclonal antibodies to selectively deliver highly potent cytotoxic drugs to tumor cells, which have become a powerful measure for cancer treatment in recent years. To develop a more effective therapy for human epidermal growth factor receptor 2 (HER2)-positive cancer, we explored a novel ADCs composed of anti-HER2 scFv–HSA fusion antibodies conjugates with a potent cytotoxic drug DM1. The resulting ADCs, T-SA1–DM1 and T-SA2–DM1 (drug-to-antibody ratio in the range of 3.2–3.5) displayed efficient inhibition in the growth of HER2-positive tumor cell lines and the half-maximal inhibitory concentration on SKBR-3 and SKOV3 cells were both at the nanomolar levels in vitro. In HER2-positive human ovarian cancer xenograft models, T-SA1–DM1 and T-SA2–DM1 also showed remarkable antitumor activity. Importantly, three out of six mice exhibited complete remission without regrowth in the high-dose group of T-SA1–DM1. On the basis of the analysis of luminescence imaging, anti-HER2 scFv–HSA fusion antibodies, especially T-SA1, showed strong and rapid tumor tissue penetrability and distribution compared with trastuzumab. Collectively, the novel type of ADCs is effective and selective targeting to HER2-positive cancer, and may be a promising antitumor drug candidate for further studies.

▲ Figure: Distribution of trastuzumab, T-SA1 and T-SA2 in vivo was displayed by bioluminescence imaging system. Both T-SA1 and T-SA2 could target tumor tissues specifically within 2 h post injection and the maximum fluorescence intensity on the area of tumor was observed at 12 h post injection. The tumor tissue areas were shown with the red arrows. The liver areas were shown with the blue arrows.

全文链接：https://www.nature.com/articles/sigtrans201715