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

Perfect Coupling of Antibodies with Small Molecule Drugs:Site-specific Conjugation for Antibody-Drug Conjugates

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-drugconjugates,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。

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 conjugation methods tbr ADCs were reviewed herein.