化学
小分子
结合
药品
组合化学
抗体-药物偶联物
TCEP
连接器
共轭体系
化学稳定性
分子
药物发现
色谱法
聚合物
抗体
磷化氢
药理学
单克隆抗体
有机化学
生物化学
医学
数学分析
数学
计算机科学
免疫学
生物
操作系统
催化作用
作者
Tao Chen,Dian Su,Jason Gruenhagen,Christine Gu,Li Yi,Peter Yehl,Nik P. Chetwyn,Colin D. Medley
标识
DOI:10.1016/j.jpba.2015.09.015
摘要
Antibody-drug conjugates (ADCs) offer new therapeutic options for advanced cancer patients through precision killing with fewer side effects. The stability and efficacy of ADCs are closely related, emphasizing the urgency and importance of gaining a comprehensive understanding of ADC stability. In this work, a chemical de-conjugation approach was developed to investigate the in-situ stability of the small molecule drug while it is conjugated to the antibody. This method involves chemical-mediated release of the small molecule drug from the ADC and subsequent characterization of the released small molecule drug by HPLC. The feasibility of this technique was demonstrated utilizing a model ADC containing a disulfide linker that is sensitive to the reducing environment within cancer cells. Five reducing agents were screened for use in de-conjugation; tris(2-carboxyethyl) phosphine (TCEP) was selected for further optimization due to its high efficiency and clean impurity profile. The optimized de-conjugation assay was shown to have excellent specificity and precision. More importantly, it was shown to be stability indicating, enabling the identification and quantification of the small molecule drug and its degradation products under different formulation pHs and storage temperatures. In summary, the chemical de-conjugation strategy demonstrated here offers a powerful tool to assess the in-situ stability of small molecule drugs on ADCs and the resulting information will shed light on ADC formulation/process development and storage condition selection.
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