title: Immune-mediated liver injury of the cancer therapeutic antibody catumaxomab targeting EpCAM, CD3 and Fcγ receptors.
abstract: The immunotherapeutic catumaxomab targets EpCAM positive cancers and is approved for the treatment of peritoneal carcinomatosis. To assess the safety of intravenous applications a phase 1 clinical trial was initiated. Treatment of EpCAM positive tumor patients with catumaxomab caused dose dependent hepatitis as evidenced by significant elevations in serum alanine- and aspartate aminotransferases, bilirubin, γGT and induction of the acute phase C-reactive protein (CRP) and the cytokines IL6 and IL8. The first patient receiving 10μg catumaxomab experienced fatal acute liver failure which led to the termination of the study. Immmunopathology revealed catumaxomab to bind via its Fc-fragment to FcγR-positive Kupffer cells to stimulate CRP, chemokine and cytokine release. The observed CD3+T-cell margination at activated hepatic macrophages exacerbated T-cell mediated cytotoxicity. Strikingly, the combined Kupffer/T-cell responses against liver cells did not require hepatocytes to be EpCAM-positive. Catumaxomab's off-target activity involved T-cell mediated lysis of the granzyme B cell death pathway and the molecular interaction of hepatic sinusoidal macrophages with T-cells induced cytolytic hepatitis. Although the bile ducts were surrounded by densely packed lymphocytes these rarely infiltrated the ducts to suggest an intrahepatic cholestasis as the cause of hyperbilirubinaemia. Lastly, evidence for the programming of memory T-cells was observed with one patient that succumbed to his cancer six weeks after the last catumaxomab infusion. In conclusion, our study exemplifies off-target hepatotoxicity with molecularly targeted therapy and highlights the complexities in the clinical development of immunotherapeutic antibodies.
authors.affiliation: Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Borlak
authors.affiliation: Department of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Länger
authors.affiliation: Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany.|Institute of Pathology, Viersen, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Spanel
authors.affiliation: Clinical Development, Fresenius Biotech GmbH, München, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schöndorfer
authors.affiliation: Applied Cancer Research - Institution for Translational Research Vienna (ACR-ITR VIEnna) and Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna), Center for Oncology and Hematology, Kaiser Franz Josef-Spital, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Dittrich
mesh_terms: D018033:Antibodies, Bispecific / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017252:CD3 Complex / Q000037:antagonists & inhibitors; D000071858:Epithelial Cell Adhesion Molecule / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D017093:Liver Failure / Q000139:chemically induced*; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D017452:Receptors, IgG / Q000037:antagonists & inhibitors
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D017252:CD3 Complex; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D017452:Receptors, IgG; C522419:catumaxomab
keywords: acute liver failure (ALF); catumaxomab; epithelial cell adhesion molecule EpCAM; idiosyncratic drug hepatotoxicity