AbbVie, North Chicago, Illinois.
Jazz Pharmaceuticals, Palo Alto, California.
Cancer Res. 2022 May 16;82(10):1858-1869. doi: 10.1158/0008-5472.CAN-21-3236.
Antibody-drug conjugates (ADC) have emerged as one of the pillars of clinical disease management in oncology. The biggest hurdle to widespread development and application of ADCs has been a narrow therapeutic index. Advances in antibody technologies and formats as well as novel linker and payload chemistries have begun to facilitate structural improvements to ADCs. However, the interplay of structural characteristics with physiologic and pharmacologic factors determining therapeutic success has garnered less attention. This review elaborates on the pharmacology of ADCs, the pathophysiology of cancerous tissues, and the reciprocal consequences on ADC properties and functions. While most currently approved ADCs utilize either microtubule inhibition or DNA damage as primary mechanisms of action, we present arguments to expand this repertoire and highlight the need for payload mechanisms that exploit disease-specific vulnerabilities. We promote the idea that the choice of antibody format, targeting antigen, linker properties, and payload of an ADC should be deliberately fit for purpose by taking the pathophysiology of disease and the specific pharmacology of the drug entity into account, thus allowing a higher probability of clinical success.
抗体偶联药物（ADC）已成为肿瘤临床疾病管理的支柱之一。ADC 广泛开发和应用的最大障碍是治疗指数较窄。抗体技术和形式的进步以及新型连接子和有效载荷化学的出现，开始促进 ADC 的结构改进。然而，结构特征与决定治疗成功的生理和药理因素之间的相互作用却没有得到太多关注。本文详细阐述了 ADC 的药理学、癌组织的病理生理学，以及对 ADC 特性和功能的相互影响。虽然目前大多数批准的 ADC 都将微管抑制或 DNA 损伤作为主要作用机制，但我们提出了扩展这一作用机制的论点，并强调需要利用疾病特异性弱点的有效载荷机制。我们提倡这样一种观点，即 ADC 的抗体形式、靶向抗原、连接子特性和有效载荷的选择应该根据疾病的病理生理学和药物实体的特定药理学进行精心设计，从而提高临床成功的可能性。
