a Genentech Research and Early Development, Genentech Inc ., South San Francisco, CA , USA.
MAbs. 2018 Oct;10(7):960-967. doi: 10.1080/19420862.2018.1494487. Epub 2018 Jul 26.
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) designed for the treatment of HER2-positive cancers. T-DM1 is composed of the humanized monoclonal antibody trastuzumab connected to a maytansine derivative cytotoxic drug, via a nonreducible thioether linker at random lysine residues, and therefore has a very complex molecular structure. It was anticipated that T-DM1 undergoes biotransformations in circulation. However, there was limited knowledge on these structural changes due to bioanalytical challenges. Here, we have investigated the in vivo biotransformations of T-DM1 using a high-resolution accurate-mass (HR/AM) mass spectrometry approach. Three types of biotransformations were characterized for T-DM1 in circulation in tumor-bearing mice, including cysteine or glutathione adduct formation via maleimide exchange, loss of maytansinol via ester hydrolysis, as well as addition of HO via linker-drug hydrolysis. These results provide new insights into in vivo catabolism of T-DM1.
曲妥珠单抗美坦新偶联物（T-DM1）是一种抗体药物偶联物（ADC），用于治疗 HER2 阳性癌症。T-DM1 由人源化单克隆抗体曲妥珠单抗与美登素衍生物细胞毒药物通过随机赖氨酸残基上的不可还原的硫醚键连接而成，因此具有非常复杂的分子结构。预计 T-DM1 在循环中会发生生物转化。但是，由于生物分析方面的挑战，对于这些结构变化的了解非常有限。在这里，我们使用高分辨率精确质量（HR/AM）质谱方法研究了 T-DM1 的体内生物转化。在荷瘤小鼠的循环中，鉴定了 T-DM1 中的三种生物转化类型，包括通过马来酰亚胺交换形成半胱氨酸或谷胱甘肽加合物、通过酯水解丢失美登醇，以及通过连接子-药物水解添加 HO。这些结果为 T-DM1 的体内代谢提供了新的见解。
