Widdison Wayne, Wilhelm Sharon, Veale Karen, Costoplus Juliet, Jones Gregory, Audette Charlene, Leece Barbara, Bartle Laura, Kovtun Yelena, Chari Ravi
ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
Mol Pharm. 2015 Jun 1;12(6):1762-73. doi: 10.1021/mp5007757. Epub 2015 Apr 8.
Several antibody-maytansinoid conjugates (AMCs) are in clinical trials for the treatment of various cancers. Each of these conjugates can be metabolized by tumor cells to give cytotoxic maytansinoid metabolites that can kill targeted cells. In preclinical studies in mice, the cytotoxic metabolites initially formed in vivo are further processed in the mouse liver to give several oxidized metabolic species. In this work, the primary AMC metabolites were synthesized and incubated with human liver microsomes (HLMs) to determine if human liver would likely give the same metabolites as those formed in mouse liver. The results of these HLM metabolism studies as well as the subsequent syntheses of the resulting HLM oxidation products are presented. Syntheses of the minor impurities formed during the conjugation of AMCs were also conducted to determine their cytotoxicities and to establish how these impurities would be metabolized by HLM.
几种抗体-美登素类缀合物（AMC）正在进行治疗各种癌症的临床试验。这些缀合物中的每一种都可以被肿瘤细胞代谢，产生具有细胞毒性的美登素类代谢物，从而杀死靶细胞。在小鼠的临床前研究中，体内最初形成的细胞毒性代谢物在小鼠肝脏中进一步加工，产生几种氧化代谢产物。在这项工作中，合成了主要的AMC代谢物，并与人肝微粒体（HLM）一起孵育，以确定人肝脏是否可能产生与小鼠肝脏中形成的代谢物相同的代谢物。本文介绍了这些HLM代谢研究的结果以及随后所得HLM氧化产物的合成。还进行了AMC缀合过程中形成的次要杂质的合成，以确定它们的细胞毒性，并确定这些杂质将如何被HLM代谢。
