通过电子激活解离来表征无基准的蒂奥-苏西尼米德异体化.
Junyan Yang1, Jiaqi Yuan1, Yue Huang1
1Integrated Bioanalysis, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, South San Francisco, California, USA.
Rapid communications in mass spectrometry : RCM
|September 17, 2024
概括
这项研究引入了一种新的方法,用于在抗体-药物结合物 (ADC) 中区分蒂奥-苏胺化水解异构体. 该技术使用质谱测量来识别特定的产品离子,帮助ADC的开发.
科学领域:
- 制药化学 制药化学 制药化学
- 分析化学 分析化学
- 生物结合化学 生物结合化学
背景情况:
- 异构在药物开发中至关重要,影响药物药理学和分子设计.
- 在抗体-药物联合体 (ADC) 中的提奥-糖胺水解产生了组成性异构体:提奥-阿斯帕提尔和提奥-异阿斯帕提尔.
- 区分这些同位素对于理解ADC的稳定性和有效性至关重要.
研究的目的:
- 开发和验证一种新的方法,用于区分thio-succinimide水解异构体.
- 在血中随着时间的推移,研究ADCs中thio-succinimide链接的异构化过程.
- 在没有参考标准的情况下建立可靠的异构体识别方法.
主要方法:
- 一种混合方法,结合了连接物结合试验 (LBA) 和液态染色学-并联质谱法 (LC-MS/MS).
- 使用了两个直角解离方法:碰撞诱导解离 (CID) 和电子激活解离 (EAD).
- 分析了由CID和EAD生成的MS/MS光谱,以识别独特的同位素签名.
主要成果:
- 通过使用EAD观察到-亚斯巴提尔和-异亚斯巴提尔异构体的明显MS/MS光谱.
- 识别的标志性产品离子,包括[R1 + Thio + 57 + H]+,[R2 + Succ + H2O - 57 + H]+,[R2 + Succ + H2O - 44 + 2H]2+.
- 一个新发现的[R2 + ThioSucc + H2O - 44 + 2H]2+离子为同位素差异化提供了进一步的证据.
结论:
- 在没有合成参考材料的情况下成功识别了thio-succinimide水解异构体.
- 开发的方法适用于各种与thio-succinimide 结合的分子.
- 准确的异构体识别将促进ADCs的开发和应用.
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