A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults.

IF 1.3 4区 医学 Q4 INFECTIOUS DISEASES
Wim Pierson, Marianne Tuefferd, Florence Herschke, Leen Slaets, Marjolein Crabbe, Dorien Verstappen, Steffi De Pelsmaeker, Ian Strickland, Edward J Gane, Christian Schwabe, Yingjie Zhang, Peter Meerts, Joris Vandenbossche, Pieter Van Remoortere, Inge Verbrugge, An De Creus
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引用次数: 0

Abstract

Background: Chronic hepatitis B (CHB) is responsible for major disease burden worldwide. However, the number of available therapies is limited; cure remains an elusive goal. JNJ-64794964 (JNJ-4964) is an oral toll-like receptor-7 (TLR7) agonist being evaluated for the treatment of CHB. Here, we investigated the capacity of JNJ-4964 to induce transcriptomic and immune cell changes in peripheral blood in healthy volunteers.

Methods: Peripheral blood was collected in the JNJ-4964 first-in-human phase 1 trial at multiple time points to assess transcriptomics and changes in frequency and phenotype of peripheral-blood mononuclear cells. Correlation of changes to JNJ-4964 exposure (Cmax) and changes in cytokine levels (C-X-C motif chemokine ligand 10 [CXCL10] and interferon alpha [IFN-α]) were evaluated.

Results: Fifty-nine genes, mainly interferon-stimulated genes, were up-regulated between 6 hours and 5 days after JNJ-4964 administration. JNJ-4964 increased frequencies of CD69, CD134, CD137, and/or CD253-expressing natural killer (NK) cells, indicative of NK cell activation. These changes correlated with Cmax, increase of CXCL10, and induction of IFN-α and were observed at IFN-α levels that are associated with no/acceptable flu-like adverse events. JNJ-4964 administration resulted in increased frequencies of CD86-expressing B cells, indicative of B-cell activation. These changes were predominantly observed at high IFN-α levels, which are associated with flu-like adverse events.

Conclusions: JNJ-4964 administration led to changes in transcriptional profiles and immune cell activation phenotype, particularly for NK cells and B cells. Together, these changes could represent a set of biomarkers for the characterization of the immune response in CHB patients receiving TLR7 agonists.

单次口服TLR7激动剂JNJ-64794964可诱导健康成人外周免疫细胞的转录组学和表型变化。
背景:慢性乙型肝炎(CHB)是世界范围内的主要疾病负担。然而,可用的治疗方法数量有限;治愈仍然是一个难以实现的目标。JNJ-64794964 (JNJ-4964)是一种口服toll样受体-7 (TLR7)激动剂,正在评估治疗慢性乙型肝炎的疗效。在这里,我们研究了JNJ-4964在健康志愿者外周血中诱导转录组和免疫细胞变化的能力。方法:在JNJ-4964首次人体1期试验中收集外周血,在多个时间点评估外周血单个核细胞的转录组学和频率和表型的变化。评估JNJ-4964暴露变化(Cmax)与细胞因子(C-X-C基序趋化因子配体10 [CXCL10]和干扰素α [IFN-α])水平变化的相关性。结果:JNJ-4964给药后6小时至5天,59个基因表达上调,主要为干扰素刺激基因。JNJ-4964增加了表达CD69、CD134、CD137和/或cd253的自然杀伤(NK)细胞的频率,表明NK细胞被激活。这些变化与Cmax、CXCL10的增加和IFN-α的诱导相关,并且在IFN-α水平与无/可接受的流感样不良事件相关时观察到。JNJ-4964导致表达cd86的B细胞频率增加,表明B细胞活化。这些变化主要在高IFN-α水平时观察到,这与流感样不良事件有关。结论:JNJ-4964给药导致转录谱和免疫细胞活化表型的变化,特别是对NK细胞和B细胞。总之,这些变化可以代表一组生物标志物,用于表征接受TLR7激动剂治疗的慢性乙型肝炎患者的免疫反应。
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来源期刊
Antiviral Therapy
Antiviral Therapy 医学-病毒学
CiteScore
2.60
自引率
8.30%
发文量
35
审稿时长
4-8 weeks
期刊介绍: Antiviral Therapy (an official publication of the International Society of Antiviral Research) is an international, peer-reviewed journal devoted to publishing articles on the clinical development and use of antiviral agents and vaccines, and the treatment of all viral diseases. Antiviral Therapy is one of the leading journals in virology and infectious diseases. The journal is comprehensive, and publishes articles concerning all clinical aspects of antiviral therapy. It features editorials, original research papers, specially commissioned review articles, letters and book reviews. The journal is aimed at physicians and specialists interested in clinical and basic research.
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