Synthesis, characterization, and targeted chemotherapy of SCT200-linker-monomethyl auristatin E conjugates

• Published in: European journal of medicinal chemistry 2021-04, Vol.216, p.113297, Article 113297
• Main Authors: Hu, Xinyue, Jiang, Hailun, Bai, Weiqi, Liu, Xiujun, Miao, Qingfang, Wang, Linlin, Jin, Jie, Cui, Along, Liu, Rui, Li, Zhuorong
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - chemistry; Antibody-drug conjugate; Antineoplastic Agents - blood; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Cathepsin B - metabolism; Cell Line, Tumor; Drug Liberation; Drug release; Drug Stability; ErbB Receptors - genetics; ErbB Receptors - immunology; ErbB Receptors - metabolism; Female; Gene Expression Regulation - drug effects; Humans; Immunoconjugates - blood; Immunoconjugates - chemistry; Immunoconjugates - pharmacology; Immunoconjugates - therapeutic use; Linker; Mice; Mice, Nude; Monomethyl auristatin E; Neoplasms - drug therapy; Neoplasms - pathology; Oligopeptides - chemistry; Oligopeptides - metabolism; Solid tumor; Xenograft Model Antitumor Assays
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113297

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. [Display omitted] •We generated three types of novel linkers for ADCs.•The activities of a subset of ADCs were increased for EGFR-positive tumors.•These linkers may be used to conjugate other antibodies to treat various cancers.