Metabolites of Antibody–Maytansinoid Conjugates: Characteristics and in Vitro Potencies

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 i...

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Bibliographic Details
Published in:Molecular pharmaceutics 2015-06, Vol.12 (6), p.1762-1773
Main Authors: Widdison, Wayne, Wilhelm, Sharon, Veale, Karen, Costoplus, Juliet, Jones, Gregory, Audette, Charlene, Leece, Barbara, Bartle, Laura, Kovtun, Yelena, Chari, Ravi
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Humans
Immunoconjugates - chemistry
Immunoconjugates - metabolism
Magnetic Resonance Spectroscopy
Maytansine - chemistry
Mice
Microsomes, Liver
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:1543-8384
1543-8392
DOI:10.1021/mp5007757