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....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.展开更多
基金financially supported by the National Science Foundation of China(nos 81372822,81402564 and 81572995)National High Technology Research and Development Program of China(no.2015AA020904)Guangdong Innovative Research Team Program(no.2011Y073).
文摘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.
