Li Meng, Zhao Xueyu, Yu Chuanfei, Wang Lan
NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, People's Republic of China.
The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing, People's Republic of China.
Pharm Res. 2024 Mar;41(3):419-440. doi: 10.1007/s11095-023-03649-z. Epub 2024 Feb 17.
Antibody-drug conjugates (ADCs) comprise an antibody, linker, and drug, which direct their highly potent small molecule drugs to target tumor cells via specific binding between the antibody and surface antigens. The antibody, linker, and drug should be properly designed or selected to achieve the desired efficacy while minimizing off-target toxicity. With a unique and complex structure, there is inherent heterogeneity introduced by product-related variations and the manufacturing process. Here this review primarily covers recent key advances in ADC history, clinical development status, molecule design, manufacturing processes, and quality control. The manufacturing process, especially the conjugation process, should be carefully developed, characterized, validated, and controlled throughout its lifecycle. Quality control is another key element to ensure product quality and patient safety. A patient-centric strategy has been well recognized and adopted by the pharmaceutical industry for therapeutic proteins, and has been successfully implemented for ADCs as well, to ensure that ADC products maintain their quality until the end of their shelf life. Deep product understanding and process knowledge defines attribute testing strategies (ATS). Quality by design (QbD) is a powerful approach for process and product development, and for defining an overall control strategy. Finally, we summarize the current challenges on ADC development and provide some perspectives that may help to give related directions and trigger more cross-functional research to surmount those challenges.
抗体药物偶联物（ADC）由抗体、连接子和药物组成，它们通过抗体与表面抗原之间的特异性结合，将其高效的小分子药物导向靶肿瘤细胞。抗体、连接子和药物应经过合理设计或选择，以实现预期疗效，同时将脱靶毒性降至最低。由于其独特而复杂的结构，产品相关变异和制造工艺会引入内在的异质性。本文综述主要涵盖了ADC在历史、临床开发状况、分子设计、制造工艺和质量控制方面的近期关键进展。制造工艺，尤其是偶联工艺，在其整个生命周期中都应仔细开发、表征、验证和控制。质量控制是确保产品质量和患者安全的另一个关键要素。以患者为中心的策略已得到制药行业对治疗性蛋白质的充分认可和采用，并且也已成功应用于ADC，以确保ADC产品在保质期结束前保持其质量。对产品的深入理解和工艺知识定义了属性测试策略（ATS）。质量源于设计（QbD）是一种用于工艺和产品开发以及定义总体控制策略的有力方法。最后，我们总结了当前ADC开发面临的挑战，并提供了一些观点，可能有助于给出相关方向并引发更多跨职能研究以克服这些挑战。
