2020 年 78 巻 5 号 p. 503-515
Antibody-drug conjugates (ADCs) are an emerging drug format of chemotherapy agents with durable therapeutic efficacy and high target specificity. They are expected to revolutionize current cancer treatment strategies and regimens. Currently, seven ADCs are approved by the U.S. Food and Drug Administration (FDA), and more than 100 ADCs are in clinical trials. ADCs consist of humanized or fully human monoclonal antibodies with extremely potent cytotoxic agents (payloads) attached via chemical linkers. The linker structure and conjugation method markedly influence ADC homogeneity, circulation stability, pharmacokinetics profile, therapeutic window, and treatment outcome. In most prior attempts to improve these parameters, linear chemical linkers were used. A disadvantage of this approach is that only one payload molecule can be incorporated per linker. However, the use of branched linkers that can incorporate multiple payload molecules has not been fully explored. In addition, the most common enzymatically cleavable linker used in current ADCs, while stable in humans, is labile in mouse circulation depending on the conjugation site and linker length. In this paper we describe branched linkers, efficient conjugation methods for constructing homogeneous branched ADCs, and a novel tripeptide linker that retains responsiveness to enzymatic drug release and stability in both mouse and human plasma. We also examine several aspects to be considered for constructing safer and more efficacious next-generation ADCs based on recent advances in the ADC field.