Frigerio Mark, Kyle Andrew F
Abzena, Babraham Research Campus, Babraham, Cambridge, CB22 3AT, United Kingdom.
Curr Top Med Chem. 2017;17(32):3393-3424. doi: 10.2174/1568026618666180118155847.
Antibody Drug Conjugates (ADCs) use targeting ability of monoclonal antibodies to deliver potent cytototoxic payloads to their intended target. The linker encompasses a conjugating functionality suitable for attachment to the antibody, a spacer unit that typically incorporates a hydrophilic element and a trigger which releases the potent cytototoxic warhead. Understanding the conflicting requirements of ADC design, providing stability in systemic circulation but efficient payload release once the ADC reaches its intended target, is crucial to effective linker development. ADC linker design has been approached in a variety of different ways, with increasingly elegant solutions continuing to be reported as understanding of the intricate design complexities increases. This review focuses on the synthetic approaches used in ADC linkers, and the impact of linker design on antibody conjugation, ADC pharmacokinetics and payload release. Linker approaches utilized in commercial ADCs as well as ADCs currently in clinical, pre-clinical and early stage development are discussed.
抗体药物偶联物（ADCs）利用单克隆抗体的靶向能力，将强效细胞毒性载荷递送至其预定靶点。连接子包含适合连接至抗体的共轭功能基团、通常含有亲水元素的间隔单元以及释放强效细胞毒性弹头的触发基团。理解ADC设计中相互矛盾的要求，即在体循环中提供稳定性，但一旦ADC到达其预定靶点就实现有效载荷释放，对于有效的连接子开发至关重要。ADC连接子设计已经采用了多种不同方法，随着对复杂设计复杂性的理解不断加深，越来越精妙的解决方案不断被报道。本综述聚焦于ADC连接子中使用的合成方法，以及连接子设计对抗体偶联、ADC药代动力学和载荷释放的影响。讨论了商业ADC以及目前处于临床、临床前和早期开发阶段的ADC中使用的连接子方法。
