title: Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity.
abstract: Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized mAb directed against HER2, and a microtubule inhibitor, DM1, conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1-induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse models to investigate the mechanisms of T-DM1-induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is colocalized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in mice and induces inflammation and necrosis in liver tissues, and that T-DM1-induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNFα in liver tissues is significantly increased in mice treated with T-DM1 as compared with those treated with trastuzumab or vehicle. We propose that T-DM1-induced upregulation of TNFα enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphologic change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1-induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs.
authors.affiliation: Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. Interagency Oncology Task Force Fellowship: Oncology Product Research/Review Fellow, NCI, Bethesda, Maryland.
authors.forename: Haoheng
authors.initials: H
authors.lastname: Yan
authors.affiliation: Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Endo
authors.affiliation: Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Division of Compliance, Office of Surveillance and Compliance, Center for Veterinary Medicine, U.S. Food and Drug Administration, Derwood, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Rotstein
authors.affiliation: Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Milos
authors.initials: M
authors.lastname: Dokmanovic
authors.affiliation: Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Nishant
authors.initials: N
authors.lastname: Mohan
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Division of Biotechnology Review and Research I, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. wen.wu@fda.hhs.gov.
authors.forename: Wen Jin
authors.initials: WJ
authors.lastname: Wu
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D015415:Biomarkers; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008453:Maytansine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D023421:Models, Animal; D009336:Necrosis / Q000188:drug therapy / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015415:Biomarkers; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D050257:Tubulin Modulators