抗体与小分子药物一体化的完美联姻——解析抗体-药物偶联物之.pdfVIP

PROGRESS IN PHARMACEUTICAL SCIENCES 2015,39 4 :283-292 ( ) 283 抗体与小分子药物一体化的完美“联姻” ——解析抗体 - 药物偶联物之定点偶联 李晨晨，王旻，张娟* ( 中国药科大学生命科学与技术学院，江苏 南京 210009) [ 摘要 ] 基于单抗的靶向疗法已成为各种癌症的重要治疗手段，抗体与小分子药物一体化的联姻——抗体—药物偶联物（antibody-drug conjugates，ADC）新药获得了突破性进展。传统 ADC 是将药物与抗体的赖氨酸残基或链间二硫键还原而产生的半胱氨酸残基相偶联 而形成，其稳定性差，易发生聚集，且其中药物易脱落而产生非治疗性毒副作用。而应用近年发展起来的定点偶联技术所获 ADC，除均 一性好外，还保留了母体单抗的药动学性质，毒副作用也远低于具有相同偶联比的传统 ADC，极有可能发展成为新一代重磅药物。综述 4 种 ADC 定点偶联方法。 [ 关键词 ] 抗体—药物偶联物；定点偶联；反应性半胱氨酸；非天然氨基酸；酶法；二硫键改造 [ 中图分类号 ] R918 [ 文献标志码 ] A [ 文章编号 ] 1001-5094（2015）04-0283-10 erfect Coupling of Antibodies with Small Molecule Drugs: P Site-specific Conjugation for Antibody-Drug Conjugates LI Chenchen, WANG Min, ZHANG Juan (School of Life Science Technology, China Pharmaceutical University, Nanjing 210009, China) [Abstract] Antibody based targeted therapy has become more and more popular in anti-cancer therapy. Coupling of antibodies with small molecule drugs——antibody-drug conjugate(ADC) which is a new class of therapeutics has got a breakthrough. Conventional conjugation methods are based on lysine and cysteine residues and the ADCs yielded by these methods have poor stability. They are prone to aggregation and the conjugated drugs are easy to shed resulting in non-therapeutic side effects. The ADCs produced by the site-specific conjugation techniques developed recently have homogeneous drug-to-antibody ratios (DAR), similar pharmacokinetics with their parental antibodies and far less side effects than those of the conventional ADC with the same DAR. So the improved ADCs are expected to become a new generation of blockbuster drugs. Four site-specific