Staudacher Alexander H, Brown Michael P
Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5000, Australia.
School of Medicine, University of Adelaide, Adelaide, SA 5000, Australia.
Br J Cancer. 2017 Dec 5;117(12):1736-1742. doi: 10.1038/bjc.2017.367. Epub 2017 Oct 24.
Antibody drug conjugates (ADCs) employ the exquisite specificity of tumour-specific monoclonal antibodies (mAb) for the targeted delivery of highly potent cytotoxic drugs to the tumour site. The chemistry of the linker, which connects the drug to the mAb, determines how and when the drug is released from the mAb. This, as well as the chemistry of the drug, can dictate whether the drug can diffuse into surrounding cells, resulting in 'bystander killing'. Initially, any bystander killing mechanism of action of an ADC was understood to involve an essential sequence of steps beginning with surface antigen targeting, internalisation, intracellular linker cleavage, drug release, and diffusion of drug away from the targeted cell. However, recent studies indicate that, depending on the linker and drug combination, this mechanism may not be essential and ADCs can be cleaved extracellularly or via other mechanisms. In this minireview, we will examine the role of bystander killing by ADCs and explore the emerging evidence of how this can occur independently of internalisation.
抗体药物偶联物（ADCs）利用肿瘤特异性单克隆抗体（mAb）的高度特异性，将强效细胞毒性药物靶向递送至肿瘤部位。连接药物与单克隆抗体的连接子化学性质，决定了药物如何以及何时从单克隆抗体中释放。这一点以及药物的化学性质，能够决定药物是否能够扩散到周围细胞中，从而导致“旁观者杀伤”。最初，人们认为ADC的任何旁观者杀伤作用机制都涉及一系列基本步骤，始于表面抗原靶向、内化、细胞内连接子裂解、药物释放以及药物从靶向细胞扩散出去。然而，最近的研究表明，根据连接子和药物的组合情况，这一机制可能并非必不可少，ADCs可以在细胞外裂解或通过其他机制裂解。在这篇小型综述中，我们将研究ADCs旁观者杀伤的作用，并探讨关于其如何能够独立于内化过程而发生的新证据。
