Anal Chem. 2020 Jun 16;92(12):8268-8277. doi: 10.1021/acs.analchem.0c00520. Epub 2020 May 22.
Complex biotherapeutics present challenges from drug discovery, screening, and development perspectives. While monoclonal antibody drugs are not monitored for metabolites in the same manner as small molecules, biotherapeutics such as fusion proteins, antibody-drug conjugates, or bispecific antibodies may undergo biotransformation (such as clipping, deamidation, or oxidation) in vivo, resulting in catabolites that can have a direct impact on drug safety or efficacy. Here antibody subunit LC-MS is utilized for evaluation of two classes of complex biotherapeutics: an antibody-drug conjugate and a mAb-fusion biotherapeutic. Pharmacokinetic concentration, biotransformation, and DAR data are collectively presented using the subunit LC-MS approach for the two molecules, and the methods shared in detail can be applied to any humanized IgG1 mAb biotherapeutic for preclinical study support. Overall, the data generated from antibody LC-MS analyses can provide key information in early phase development and deliver multiple study end points with a single data set.
复杂的生物疗法在药物发现、筛选和开发方面带来了挑战。虽然单克隆抗体药物不像小分子药物那样监测其代谢物，但融合蛋白、抗体药物偶联物或双特异性抗体等生物疗法可能会在体内发生生物转化（如剪接、脱酰胺或氧化），从而产生对药物安全性或疗效有直接影响的代谢产物。在这里，抗体亚基 LC-MS 用于评估两类复杂的生物疗法：抗体药物偶联物和 mAb 融合生物疗法。使用亚基 LC-MS 方法对这两种分子进行了药代动力学浓度、生物转化和 DAR 数据的综合评估，并且详细共享的方法可以应用于任何用于临床前研究支持的人源化 IgG1 mAb 生物疗法。总体而言，抗体 LC-MS 分析产生的数据可以在早期开发阶段提供关键信息，并通过单个数据集提供多个研究终点。
