Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985)

Autor: Dongke Yu, Jiangyou Shi, Chun Guo, Rongsheng Tong, Peidu Jiang, Zhongliang Jiang, Yuxuan Zhu, Lu Chen, Dandan Guo, Zhuyu Xu, Lan Bai
Rok vydání: 2019
Předmět:
Zdroj: European Journal of Medicinal Chemistry. 183:111682
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2019.111682
Popis: Targeted drug delivery has improved cancer treatment significantly in recent years, although it is difficult to achieve. Different approaches have been developed to apply targeted drug delivery. Among which, antibody-drug conjugate (ADC) provides a potentially ideal solution to such a challenge. ADC is an innovative drug treatment model with three key components: payload, monoclonal antibody, and linker. The monoclonal antibody targets the antigen-expressing tumor cells and internalizes the payload linked by the linker to the target cells to reduce the side effects of the traditional chemotherapy drugs. The off-target effect has an excellent therapeutic prospect. Among them, ado-trastuzumab emtansine (T-DM1) is a successful example of targeting human epidermal growth factor receptor-2 (HER2). Its antibody (trastuzumab) is derived from Herceptin with annual sales of more than $6 billion. It has excellent targeting and specific anti-tumor activity against HER2. Its linker is not cleavable and releases the Lys-linker-payload to kill the cells. The two ADCs described here use the same antibody as T-DM1, but the cleavable linker and the more toxic payload allow them to have the not only targeting of T-DM1, but also the reduce T-DM1 resistance and improve efficacy in heterogeneous tumors. This paper describes the mechanism of action and the biochemical characteristics of different parts and preclinical and clinical progress of trastuzumab deruxtecan(DS-8201a) and (vic-)trastuzumab duocarmazine (SYD985).
Databáze: OpenAIRE
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