BACE 抑制剂阿塔贝克斯特治疗后肝损伤患者的药物特异性 T 细胞反应。

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

机构信息

MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.

Drug Metabolism and Pharmacokinetics, Janssen R&D, Beerse, Belgium.

出版信息

Allergy. 2021 Jun;76(6):1825-1835. doi: 10.1111/all.14652. Epub 2020 Nov 24.

DOI:10.1111/all.14652

PMID:33150583

Abstract

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.

摘要

背景

阿他贝斯特是一种口服 BACE 抑制剂，用于治疗阿尔茨海默病。在一些临床试验患者中，检测到肝酶升高，导致药物开发项目终止。对阿他贝斯特介导的肝损伤指数病例的肝组织进行免疫组织化学特征分析显示，T 淋巴细胞浸润在肝细胞损伤区域。再加上肝损伤延迟发生的事实，这表明适应性免疫系统可能参与了发病机制。本研究旨在从肝损伤患者中产生和鉴定阿他贝斯特（代谢物）反应性 T 细胞克隆。

方法

用阿他贝斯特及其代谢物（二氨基噻嗪[DIAT]、N-乙酰-DIAT 和环氧化物）培养外周血单核细胞，并在一些患者中尝试克隆。根据 T 细胞表型、功能、T 细胞激活途径和与结构相关化合物的交叉反应性，对阿他贝斯特（代谢物）反应性克隆进行分析。

结果

在 8 名患者中的 5 名（克隆效率高达 4.5%）检测到与 DIAT 代谢物激活的 CD4 T 细胞克隆。数量较少的 CD4 和 CD8 克隆对阿他贝斯特表现出反应性。克隆在阿他贝斯特或 DIAT 刺激后增殖并分泌 IFN-γ、IL-13 和细胞毒性分子。某些阿他贝斯特和 DIAT 反应性克隆与 N-乙酰-DIAT 交叉反应；然而，阿他贝斯特和 DIAT 之间没有观察到交叉反应。CD4 克隆通过直接、可逆的化合物-HLA Ⅱ类相互作用被激活，不需要蛋白质加工。