title: Metabolites of antibody-maytansinoid conjugates: characteristics and in vitro potencies.
abstract: 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.
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Wayne
authors.initials: W
authors.lastname: Widdison
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Sharon
authors.initials: S
authors.lastname: Wilhelm
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Veale
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Juliet
authors.initials: J
authors.lastname: Costoplus
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Jones
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Charlene
authors.initials: C
authors.lastname: Audette
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Leece
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Bartle
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kovtun
authors.affiliation: ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Chari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008453:Maytansine / Q000737:chemistry*; D051379:Mice; D008862:Microsomes, Liver; D023041:Xenograft Model Antitumor Assays
chemical_list: D018796:Immunoconjugates; D008453:Maytansine
keywords: ADC; DM1; DM4; antibody; conjugate; drug; liver; maytansinoid; metabolism; microsome