Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; National Institutes for Food and Drug Control, Beijing, 102629, China.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Eur J Med Chem. 2021 Apr 15;216:113297. doi: 10.1016/j.ejmech.2021.113297. Epub 2021 Feb 24.
Antibody-drug conjugates (ADCs) are currently among the most successful and important strategies for treating patients with solid tumors. ADCs are composed of a monoclonal antibody and warhead, which are conjugated via a linker. Currently, monomethyl auristatin E (MMAE) is the most widely applied warhead in the development of ADCs. However, MMAE-based ADCs are generally constructed using the MC-VC-PABC linker, and this design has limited structural diversity and some disadvantages. Accordingly, in this study, we generated three types of novel linker-MMAE (with alterations in the spacer, catabolizing area, and self-immolative compared with MC-VC-PABC-MMAE) in ADCs, termed SCT200-linker-MMAE conjugates, and then evaluated the linker-drug plasma stability and the rate of drug release by cathepsin B. The binding ability, internalization rates, and efficacy of all SCT200-linker-MMAE ADCs were systematically studied, and the expression of apoptosis-associated proteins and the therapeutic efficacies of SCT200-M-2, -C-2, and -C-4 were evaluated. The results showed that the activities of some of these ADCs were increased for epidermal growth factor receptor-positive tumors. Moreover, the novel linkers designed in this study can be linked with other antibodies to treat other types of cancer. Overall, these findings provide important insights into the application of SCT200-based linkers in ADCs.
抗体药物偶联物（ADCs）是目前治疗实体瘤患者最成功和最重要的策略之一。ADCs 由单克隆抗体和弹头组成，通过连接子连接。目前，单甲基澳瑞他汀 E（MMAE）是 ADC 开发中应用最广泛的弹头。然而，基于 MMAE 的 ADC 通常使用 MC-VC-PABC 连接子构建，这种设计具有有限的结构多样性和一些缺点。因此，在本研究中，我们在 ADC 中生成了三种新型连接子-MMAE（与 MC-VC-PABC-MMAE 相比，在间隔区、代谢区和自毁部分有改变），称为 SCT200-连接子-MMAE 缀合物，然后通过组织蛋白酶 B 评估了连接子-药物的血浆稳定性和药物释放率。我们系统地研究了所有 SCT200-连接子-MMAE ADC 的结合能力、内化率和功效，并评估了 SCT200-M-2、-C-2 和 -C-4 的凋亡相关蛋白表达和治疗效果。结果表明，这些 ADC 的一些活性在表皮生长因子受体阳性肿瘤中增加。此外，本研究设计的新型连接子可以与其他抗体连接，用于治疗其他类型的癌症。总之，这些发现为 SCT200 基连接子在 ADC 中的应用提供了重要的见解。
