抗体偶联药物合成过程中定点偶联技术的前沿进展

Advances in Site-specific Conjugation Technologies Applied to the Synthesis of Antibody-Drug Conjugates

关键词:  抗体偶联药物  定点偶联  生物学活性  靶向治疗

Key words:  antibody-drug conjugates  site-specific conjugation  biological activity  targeted therapy

摘要:

抗体偶联药物(antibody-drug conjugate，ADC)作为一种用于治疗肿瘤的新型药物，在过去的几十年已获长足进步。然而，由于ADC的异质性，它在临床治疗中仍然面临着各种问题和挑战。因此，定点偶联技术成为ADC药物研究的重要领域，近年来该领域取得了许多突破性进展，这赋予了ADC更优异的性能。本文系统全面地概述了ADC定点偶联技术领域的前沿进展，包括赖氨酸、半胱氨酸、低丰度氨基酸、聚糖定点偶联技术以及非天然氨基酸掺入、酶介导定点偶联技术等7个大类，详细介绍了THIOMAB技术、关键点定向修饰技术等21种经典和新兴的ADC偶联技术，以期为下一代ADC开发提供参考。

Abstract:

Antibody-drug conjugates(ADCs), as an emerging therapy for cancer treatment, have made significant progress in the past few decades. However, due to the heterogeneity of ADCs, they still face various issues and challenges in clinical therapy. Therefore, site-specific conjugation techniques have become a crucial area of research in ADCs, and in recent years, this field has witnessed numerous breakthrough advancements, empowering ADCs with enhanced performance. The review provides a comprehensive overview of the frontiers in site-specific conjugation technologies for ADCs. Categorized into seven major classes including lysine-based, cysteine-based, low-abundance amino acid-based and glycosylation site-based conjugation techniques, ribosomal incorporation of unnatural and noncanonical amino acids and enzyme-mediated conjugation techniques, it meticulously describes 21 classical and emerging techniques such as the THIOMAB technology and linchpin-directed modification, in order to offer valuable insights for the development of next-generation ADCs.