抗体药物偶联物(ADC)药动学研究的认识

Understanding of pharmacokinetic study of antibody drug conjugates

抗体药物偶联物(ADC)是由具有靶向特异性的单抗和具有高毒性的小分子结合而成的新药,与单抗和小分子药物相比,具有特异性高和毒性低的特征。由于这种特性,用于ADC的药动学(PK)研究的生物分析方法的建立和选择具有挑战性。同时大分子抗体和小分子组分的药物,生物分析方法的组合对了解ADC的体外与体内过程,认识药物运送到作用部位和暴露反应关系十分重要。因此,对ADC的开发策略、新生物分析方法的开发、建立和验证,以及临床前和临床PK、PK/PD研究的问题的挑战和机遇必须有足够认识。就ADC的药动学研究的进展和难点予以介绍,以期与从事该类药物的研究者一起讨论和分析。

Antibody drug conjugate（ADC） therapeutics utilized the specificity of monoclonal antibodies（mAbs） and potency of highly toxic small molecules. ADCs are typically composed of an mAb with a cytotoxin conjugated to it, resulting in a new eterogeneous mixture of mAb with various numbers of toxins. Due to this heterogeneity characterized by the therapeutic drug-to-antibody ratio, the selection of bioanalytical methods used to understand and develop ADCs can be challenging. Since the therapeutic drugs have both large- and small-molecule components, and one can use bioanalytical methods in both spaces. A combination of bioanalytical methods is typically used to understand the ADC in vitro/in vivo, to understand payload delivery to the site of action, and to establish an exposure-response relationship. Therefore, many challenges and opportunities to learn are involved with this approach, including issues related to ADC analysis strategies and application of these methods to ADC development, analytical establishment and validation, preclinical and clinical PK, PK/PD studies. In this paper, we introduced the progress and difficulties on pharmacokinetic studies of the ADC in order to engage researchers to discuss and analyze the issues on ADC pharmacokinetic studies.