Drug-specific T-cell responses in patients with liver injury following treatment with the BACE inhibitor atabecestat.

Autor: Thomson PJ; MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK., Kafu L; MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK., Meng X; MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK., Snoeys J; Drug Metabolism and Pharmacokinetics, Janssen R&D, Beerse, Belgium., De Bondt A; Discovery Sciences, Janssen R&D, Beerse, Belgium., De Maeyer D; Discovery Sciences, Janssen R&D, Beerse, Belgium., Wils H; Discovery Sciences, Janssen R&D, Beerse, Belgium., Leclercq L; Drug Metabolism and Pharmacokinetics, Janssen R&D, Beerse, Belgium., Vinken P; Non-Clinical Safety, Janssen R&D, Beerse, Belgium., Naisbitt DJ; MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Jazyk: angličtina
Zdroj: Allergy [Allergy] 2021 Jun; Vol. 76 (6), pp. 1825-1835. Date of Electronic Publication: 2020 Nov 24.
DOI: 10.1111/all.14652
Abstrakt: Background: Atabecestat is an orally administered BACE inhibitor developed to treat Alzheimer's disease. Elevations in hepatic enzymes were detected in a number of in trial patients, which resulted in termination of the drug development programme. Immunohistochemical characterization of liver tissue from an index case of atabecestat-mediated liver injury revealed an infiltration of T-lymphocytes in areas of hepatocellular damage. This coupled with the fact that liver injury had a delayed onset suggests that the adaptive immune system may be involved in the pathogenesis. The aim of this study was to generate and characterize atabecestat(metabolite)-responsive T-cell clones from patients with liver injury.
Methods: Peripheral blood mononuclear cells were cultured with atabecestat and its metabolites (diaminothiazine [DIAT], N-acetyl DIAT & epoxide) and cloning was attempted in a number of patients. Atabecestat(metabolite)-responsive clones were analysed in terms of T-cell phenotype, function, pathways of T-cell activation and cross-reactivity with structurally related compounds.
Results: CD4 + T-cell clones activated with the DIAT metabolite were detected in 5 out of 8 patients (up to 4.5% cloning efficiency). Lower numbers of CD4 + and CD8 + clones displayed reactivity against atabecestat. Clones proliferated and secreted IFN-γ, IL-13 and cytolytic molecules following atabecestat or DIAT stimulation. Certain atabecestat and DIAT-responsive clones cross-reacted with N-acetyl DIAT; however, no cross-reactivity was observed between atabecestat and DIAT. CD4 + clones were activated through a direct, reversible compound-HLA class II interaction with no requirement for protein processing.
Conclusion: The detection of atabecestat metabolite-responsive T-cell clones activated via a pharmacological interactions pathway in patients with liver injury is indicative of an immune-based mechanism for the observed hepatic enzyme elevations.
(© 2020 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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