Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, 77054, USA.
Protein Cell. 2018 Jan;9(1):33-46. doi: 10.1007/s13238-016-0323-0. Epub 2016 Oct 14.
The antibody-drug conjugate (ADC), a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules (payloads) through chemical linkers, is a novel therapeutic format and has great potential to make a paradigm shift in cancer chemotherapy. This new antibody-based molecular platform enables selective delivery of a potent cytotoxic payload to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and preferable pharmacokinetics (PK)/pharmacodynamics (PD) and biodistribution compared to traditional chemotherapy. Boosted by the successes of FDA-approved Adcetris and Kadcyla, this drug class has been rapidly growing along with about 60 ADCs currently in clinical trials. In this article, we briefly review molecular aspects of each component (the antibody, payload, and linker) of ADCs, and then mainly discuss traditional and new technologies of the conjugation and linker chemistries for successful construction of clinically effective ADCs. Current efforts in the conjugation and linker chemistries will provide greater insights into molecular design and strategies for clinically effective ADCs from medicinal chemistry and pharmacology standpoints. The development of site-specific conjugation methodologies for constructing homogeneous ADCs is an especially promising path to improving ADC design, which will open the way for novel cancer therapeutics.
抗体药物偶联物（ADC）是一种通过化学连接子将人源化或人源单克隆抗体与高细胞毒性小分子（有效载荷）偶联而成的新型治疗制剂，具有在癌症化疗中带来范式转变的巨大潜力。这种新的抗体为基础的分子平台使能够将有效的细胞毒性有效载荷选择性地递送到靶癌细胞，从而与传统化疗相比，提高疗效、降低全身毒性、更好的药代动力学（PK）/药效动力学（PD）和生物分布。在 FDA 批准的 Adcetris 和 Kadcyla 的成功推动下，这种药物类别与目前正在临床试验中的约 60 种 ADC 一起迅速发展。在本文中，我们简要回顾了 ADC 的每个组成部分（抗体、有效载荷和连接子）的分子方面，然后主要讨论了连接和连接子化学的传统和新技术，以成功构建临床上有效的 ADC。目前在连接和连接子化学方面的努力将从药物化学和药理学的角度为临床上有效的 ADC 提供更大的分子设计和策略见解。用于构建均一 ADC 的定点偶联方法学的发展是改善 ADC 设计的一个特别有前途的途径，这将为新型癌症治疗开辟道路。
