Emerging Chemical Modalities, Sanofi, Chilly-Mazarin, France.
Immuno-Oncology Therapeutic Area, Sanofi, Vitry-sur-Seine, France.
SLAS Discov. 2020 Sep;25(8):843-868. doi: 10.1177/2472555220912955. Epub 2020 Mar 20.
The targeted delivery of potent cytotoxic molecules into cancer cells is considered a promising anticancer strategy. The design of clinically effective antibody-drug conjugates (ADCs), in which biologically active drugs are coupled through chemical linkers to monoclonal antibodies, has presented challenges for pharmaceutical researchers. After 30 years of intensive research and development activities, only seven ADCs have been approved for clinical use; two have received fast-track designation and two breakthrough therapy designation from the Food and Drug Administration. There is continued interest in the field, as documented by the growing number of candidates in clinical development. This review aims to summarize the most recent innovations that have been applied to the design of ADCs undergoing early- and late-stage clinical trials. Discovery and rational optimization of new payloads, chemical linkers, and antibody formats have improved the therapeutic index of next-generation ADCs, ultimately resulting in improved clinical benefit for the patients.
将有效细胞毒性分子靶向递送至癌细胞被认为是一种很有前途的抗癌策略。通过化学连接子将生物活性药物偶联到单克隆抗体的抗体药物偶联物（ADC）的设计，给制药研究人员带来了挑战。经过 30 年的密集研究和开发活动，只有七种 ADC 被批准用于临床使用；其中两种已被美国食品和药物管理局（FDA）授予快速通道指定和两种突破性治疗指定。随着临床开发中候选药物数量的不断增加，该领域的持续关注有案可查。本综述旨在总结最近应用于早期和晚期临床试验中的 ADC 设计的创新。新有效载荷、化学连接子和抗体形式的发现和合理优化提高了下一代 ADC 的治疗指数，最终为患者带来了更好的临床获益。
