State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China; Research Center for Public Health and Preventive Medicine, West China School of Public Health/No.4 West China Teaching Hospital, Sichuan University, PR China; Guangdong Zhongsheng Pharmaceutical Co., Ltd., PR China.
State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
J Control Release. 2015 Dec 28;220(Pt A):5-17. doi: 10.1016/j.jconrel.2015.09.058. Epub 2015 Oct 9.
Antibody-drug conjugates (ADCs), combining monoclonal antibody with high cytotoxicity chemotherapeutic drug (warhead), have been successfully applied for clinical cancer therapy. Linker technology to select and design linker connecting warhead with antibody, is critical to the success of therapeutic ADCs. In this study, three kinds of linkers were designed to connect SN-38, the bioactive metabolite of the anticancer drug irinotecan (CPT-11), which is 100-1000 times more potent than CPT-11, with the anti-HER2 antibody trastuzumab to prepare three different ADC conjugates (T-SN38 A, B and C). Meanwhile, we compared the anti-ovarian cancer effect of these three T-SN38 conjugates with trastuzumab in vitro and in vivo. Our in vitro results showed that T-SN38 A, B and C (drug-to-antibody ratio, DAR=3.7, 3.2, 3.4) were 2 to 3 times as cytotoxic as SN-38, and the IC50 for these three conjugates on SKOV-3 cell line at 72 h were 5.2 ± 0.3, 4.4 ± 0.7, and 5.1 ± 0.4 nM respectively. In our in vivo studies, T-SN38 conjugates had well targeting ability for tumor tissue and all three of them had much higher anti-ovarian cancer potency than trastuzumab. Among of them, T-SN38 B, which coupled SN-38 with trastuzumab by a carbonate bond, has the best anti-ovarian cancer potency. In conclusion, the novel HER2-targeting ADCs T-SN38 have great potential for HER2-positive ovarian cancer. Moreover, the SN-38-Linkers designed in this study can also be used to connect with other antibodies for the therapy of other cancers.
抗体药物偶联物（ADCs）将单克隆抗体与高细胞毒性化疗药物（弹头）结合，已成功应用于临床癌症治疗。选择和设计连接弹头与抗体的连接子技术对于治疗性 ADC 的成功至关重要。在这项研究中，设计了三种连接子将伊立替康（CPT-11）的生物活性代谢物 SN-38 连接到抗 HER2 抗体曲妥珠单抗上，以制备三种不同的 ADC 缀合物（T-SN38 A、B 和 C）。同时，我们比较了这三种 T-SN38 缀合物与曲妥珠单抗在体外和体内对卵巢癌细胞的抗癌作用。我们的体外结果表明，T-SN38 A、B 和 C（药物抗体比，DAR=3.7、3.2、3.4）的细胞毒性是 SN-38 的 2 到 3 倍，这三种缀合物在 SKOV-3 细胞系上 72 小时的 IC50 值分别为 5.2±0.3、4.4±0.7 和 5.1±0.4 nM。在我们的体内研究中，T-SN38 缀合物对肿瘤组织具有良好的靶向能力，并且它们三者对卵巢癌的抗癌效力均明显高于曲妥珠单抗。其中，通过碳酸酯键将 SN-38 与曲妥珠单抗偶联的 T-SN38 B 具有最佳的抗卵巢癌效力。总之，新型 HER2 靶向 ADC T-SN38 对 HER2 阳性卵巢癌具有巨大的潜力。此外，本研究设计的 SN-38 连接子还可以用于与其他抗体结合，用于治疗其他癌症。
