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化学进展 2014, Vol. 26 Issue (0203): 467-477 DOI: 10.7536/PC130650 前一篇   后一篇

• 综述与评论 •

抗体药物偶联物

曹刚1, 黄祚刚1, 程杰飞*2, 姜标*1,3,4   

  1. 1. 中国科学院上海高等研究院 上海 201210;
    2. 大冢(上海)药物研究开发有限公司 上海 201210;
    3. 中国科学院上海有机化学研究所 上海 200032;
    4. 上海科技大学免疫化学研究所 上海 200031
  • 收稿日期:2013-06-01 修回日期:2013-10-01 出版日期:2014-02-15 发布日期:2013-12-18
  • 通讯作者: 程杰飞，e-mail：jiangb@sari.ac.cn；姜标，e-mail：jay.cheng@osri.otsuka.com E-mail:jiangb@sari.ac.cn；jay.cheng@osri.otsuka.com
  • 基金资助:

    国家自然科学基金项目（No. 20832007）资助

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Antibody-Drug Conjugates

Cao Gang1, Huang Zuogang1, Cheng Jiefei*2, Jiang Biao*1,3,4   

  1. 1. Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China;
    2. Otsuka Shanghai Research Institute, Shanghai 201210;
    3. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;
    4. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 200031, China
  • Received:2013-06-01 Revised:2013-10-01 Online:2014-02-15 Published:2013-12-18
  • Supported by:

    The work was supported by the National Natural Science Foundation of China (No.20832007)

单克隆抗体（单抗）药物是发展最为迅速的一个领域，在过去25年间大约有近30个单抗药物面世，主要用于抗癌和炎症；最近一种新的抗体药物偶联物（antibody-drug conjugate，ADC）技术取得了极大的成功。ADC是通过一个特殊的化学单元将单抗和小分子药物连接起来，充分利用抗体原有的亲合性和选择性，以及小分子药物的强药效，来降低小分子药物的毒性或延长小分子化合物的半衰期。随着一些链接技术的成熟和ADC药物上市，未来ADC将成为治疗疾病的重要手段。为了成功研制出一个新的ADC，需要对单抗、小分子药物和链接进行不断优化。一些新技术的问世也将极大促进ADC的发展。

关键词： 抗体药物偶联物, 链接, 单抗, 小分子药物

Over 35 monoclonal antibody drugs have been marketed since the approval of first monoclonal antibody drug in 1986, making the antibody drug development one of the most exciting fields. Antibody-drug conjugate (ADC), which combines a monoclonal antibody (mAb) with a cytotoxic (drug) molecule through a linker and thereby the name, is a new class of highly potent biopharmaceutical drugs designed as a targeted therapy. ADC takes advantage of the high binding specificity of mAbs and superior efficacy of cytotoxic molecules, while avoiding the dose-limiting toxicity of cytotoxic molecules. The first ADC, Mylotarg, was approved in 2000, which was late withdrawn by the manufacture due to the lack of appropriate stability of the linker. So far, there are two approved ADCs in the market for cancer therapy and over twenty ADCs in various stages of clinical trials. Creating a successful antibody drug conjugate requires careful selection of the drug, antibody and linker. Linker has a great influence on a conjugate's biological characteristics, such as stability in circulation and drug release at the target site. ADCs have been proven to be effective weapons against cancers and will certainly become useful therapeutics against other diseases.

Contents
1 Introduction
1.1 Approved ADC
1.2 ADC in clinical trials
2 Choose the right antibody
3 Choose the right cytotoxic small molecule
4 Choose the right linker
4.1 Chemical labile linker
4.2 Enzyme labile linker
4.3 Noncleavable linker
4.4 Other linkers
5 Conclusions and outlook

Key words: antibody-drug conjugate (ADC), linker, mAbs, cytotoxic molecules

中图分类号: 

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[1] 董缙 姚硕蔚 徐云根. 肿瘤血管生成抑制剂*[J]. 化学进展, 2010, 22(10): 1993-2002.
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摘要

抗体药物偶联物