差示扫描量热法在抗体偶联药物稳定性研究中的应用  

Application of differential scanning calorimetry in research on stability of antibody drug conjugate

作　　者：谭小钉[1] 章燕珍 杜翊 TAN Xiao-ding, ZHANG Yan-zhen, DU Yi(Central Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 200237, Chin)

机构地区：[1]上海医药集团股份有限公司中央研究院,上海200237

出　　处：《中国生物制品学杂志》2018年第3期299-302,306,共5页Chinese Journal of Biologicals

摘　　要：目的应用差示扫描量热法(differential scanning calorimetry,DSC)对抗体偶联药物(antibody drug conjugate,ADC)进行热稳定性考察,分析ADC药物在偶联前后的热稳定性变化及在不同溶液条件下的热稳定性差异,为制剂处方的筛选提供参考。方法通过DSC热稳定性、小分子脱落比率、SEC-HPLC纯度、与抗原结合活性等指标对曲妥珠(Trastuzumab)抗体偶联物在不同pH、不同浓度和不同类型缓冲盐、不同浓度和不同类型保护剂条件下进行加速稳定性考察。结果在4.5<pH<5.5、琥珀酸钠缓冲盐浓度≤10 mmol/L、蔗糖或海藻糖浓度>2%条件下,曲妥珠抗体偶联药物的稳定性较好。结论 DSC作为一种快速稳定性考察方法能够迅速缩小筛选范围,但在不同pH条件下,抗体偶联分子整体的热稳定性趋势与连接子(linker)的稳定趋势不一致。Objective To investigate the thermal stability of antibody drug conjugate（ADC） by differential scanning calorimety（DSC）,and analyze the change of thermal stability of ADC before and after coupling as well as the difference of thermal stabilities under various solution conditions so as to provide a reference for further screening of formula of the ADC. Methods Trastuzumab conjugate was investigated for accelerated stability at different pH values,different types and concentrations of buffered salts as well as different types and concentrations of protective agents using thermal stability of DSC,small molecule shedding ratio,SEC-HPLC purity and antigen binding activity as indicators. Results Trastuzumab conjugate showed high stability at pH value of more than 4. 5 but less than 5. 5,a sodium succinate buffer concentration of not more than 10 mmol/L and sucrose or trehalose concentration of more than 2%. Conclusion DSC was a rapid method for study on stability,by which the screening range was narrowed quickly. However,at different pH values,the trend of overall thermal stability of antibody conjugates was inconsistent with that of the linker.

关 键 词：曲妥珠 曲妥珠抗体偶联物 差示扫描量热法 抗体偶联药物 稳定性 

分 类 号：R392-33[医药卫生—免疫学]