基于定点偶联技术的抗体药物偶联物的临床研究进展与挑战

抗体药物偶联物是一类能够有效提高治疗指数的新一代抗肿瘤药物。传统的抗体药物偶联物使用非定点偶联技术，得到偶联位置和数目高度不均一的异质体，产品结构不均一，给产品质量的批间一致性控制带来挑战。定点偶联技术可以将小分子药物定点、定量地连接到抗体上，具有更好的药代动力学特性。简要总结了抗体药物偶联物的关键组成部分，抗体药物偶联物的特征，以及抗体药物偶联物的发展历史和9个已上市抗体药物偶联物，重点综述临床在研药物所使用的五大类定点偶联技术，总结处于临床研究阶段的基于定点偶联技术的抗体药物偶联物的临床数据，并展望这类技术的应用前景。

Clinical Research Progress and Challenges of Antibody-drug Conjugates Based on Site-specific Conjugation Techniques

Antibody-drug conjugates (ADCs) are considered next generation anti-cancer agents that improve therapeutic index. Traditional ADC using non-site-specific conjugation technique is a heterogenous mixture with different conjugation sites and carrying different numbers of drugs per antibody. The final ADC product contains different molecular structures with challenges to batch-to-batch consistency in product quality. The site-specific conjugation techniques have been developed to attach potent chemical drugs to defined sites of an antibody, which leads to homogeneous ADCs with better pharmacokinetics. In this article, we briefly summarize key components of ADCs, ADC characteristics, the development history for ADCs as well as the 9 approved ADCs, with focus on 5 major site-specific conjugation techniques leading to ADC products for clinical trials. Additionally, we summarize the clinical outcomes of ADCs based on site-specific conjugation techniques, with a prospect of their future application.