抗体偶联药物的技术现状和展望

抗体偶联药物（antibody drug conjugate,ADC）通常由抗体通过链接体与毒素小分子偶联而成，同时具备抗体的高靶向性和小分子药物的高活性，使之作为一种新兴的靶向治疗手段，在肿瘤治疗领域展现出了优秀的疗效和潜力，成为药物研发领域的新热点。目前全球已有14款ADC药物获批上市，处于临床研究阶段的ADC候选药物分子超过140个。为了进一步提高ADC药物的安全性和有效性，近年来涌现出了各种新颖的技术。本文对ADC药物分子的关键元素，包括抗体、链接体、毒素小分子以及偶联技术等方面的最新研究进展进行总结，并讨论其优缺点。期望这些讨论能够帮助增加对ADC药物研究和开发更加系统的理解，为研发出更加高效和安全的ADC药物带来一些思考。

Technology Advancement in Development of Antibody Drug Conjugates

Antibody drug conjugate (ADC) is typically composed of a monoclonal antibody conjugated with a cytotoxic small molecule drug via a linker. It is an emerging and promising class of targeted cancer therapeutics, combining both the highly cytotoxic activity of chemical drugs and highly targeting ability and specificity of monoclonal antibody. Fourteen ADCs have been approved for marketing so far worldwide, and more than 140 ADC drug candidates have been investigated in clinical studies. Various ADC technologies have been well developed to manufacture these ADC drugs in commercial scale as well as clinical scale. In this review, we describe the molecular structure, mechanisms of action and development history of ADCs. We then provide an overview of the current landscape and recent advances in each key element of ADCs, including antibody, linker, payload and conjugation, and their advantages and disadvantages. Future directions in ADC development may encompass smaller sized forms of antibodies such as antibody fragments and nanobodies to improve the penetration and accumulation of ADCs in the solid tumors. Novel linkers are also being tested to enhance the stability in circulation systems and reduce off-target toxicities. Emerging payloads of new functional mechanisms are also explored in the construction of ADCs to overcome the drug resistance resulted from currently used payloads of marketed ADCs. Various site-specific conjugation technologies have been adopted to reduce the heterogeneity of drug-load species and optimize the pharmacokinetic properties of ADCs. This review article aims to enhance systemic understanding and careful considerations in designing an ADC drug with improved efficacy and safety.