Toll样受体8激动剂GS-9688在慢性乙型肝炎的土拨鼠模型中诱导

StephenW

Hepatology. 2020 Apr 4. doi: 10.1002/hep.31255. [Epub ahead of print]
Toll-Like Receptor 8 Agonist GS-9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B.
Daffis S1, Balsitis S1, Chamberlain J1,2, Zheng J1, Santos R1, Rowe W1, Ramakrishnan D1, Pattabiraman D1, Spurlock S1,3, Chu R1, Kang D1, Mish M1, Ramirez R1, Li L1, Li B1, Ma S1, Hung M1, Voitenleitner C1,4, Yon C5, Suresh M5, Menne S5, Cote P5, Delaney WE 4th1, Mackman R1, Fletcher SP1.
Author information

1
    Gilead Sciences, Inc, Foster City, CA, USA.
2
    Horizon Therapeutics, South San Francisco, CA, USA.
3
    Calithera Biosciences, South San Francisco, CA, USA.
4
    Vaudaux-Eppendorf AG, Schönenbuch, Switzerland.
5
    Georgetown University Medical Center, Washington, D.C, USA.

Abstract

GS-9688 (selgantolimod) is an oral selective small molecule agonist of toll-like receptor 8 (TLR8) in clinical development for the treatment of chronic hepatitis B (CHB). In this study, we evaluated the antiviral efficacy of GS-9688 in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to hepatitis B virus (HBV). WHV-infected woodchucks received eight weekly oral doses of vehicle, 1 mg/kg GS-9688 or 3 mg/kg GS-9688. Vehicle and 1 mg/kg GS-9688 had no antiviral effect, whereas 3 mg/kg GS-9688 induced a >5 log10 reduction in serum viral load and reduced WHV surface antigen (WHsAg) levels to below the limit of detection in half of the treated woodchucks. In these animals, the antiviral response was maintained until the end of the study (>5 months after the end of treatment). GS-9688 treatment reduced intrahepatic WHV RNA and DNA levels by >95% in animals in which the antiviral response was sustained after treatment cessation, and these woodchucks also developed detectable anti-WHsAg antibodies. The antiviral efficacy of weekly oral dosing with 3 mg/kg GS-9688 was confirmed in a second woodchuck study. The antiviral response to GS-9688 did not correlate with systemic GS-9688 or cytokine levels but was associated with transient elevation of liver injury biomarkers and enhanced proliferative response of peripheral blood mononuclear cells (PBMC) to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells (TFH ) and various other immune cell subsets may play a role in the antiviral response to GS-9688. CONCLUSION: Finite, short-duration treatment with a clinically relevant dose of GS-9688 is well tolerated and can induce a sustained antiviral response in WHV-infected woodchucks. The identification of a baseline intrahepatic transcriptional signature associated with response to GS-9688 treatment provides insights into the immune mechanisms that mediate this antiviral effect.

This article is protected by copyright. All rights reserved.
KEYWORDS:

Hepatitis B virus; Selgantolimod; TFH; TLR8; Vesatolimod

PMID:
    32246499
DOI:
    10.1002/hep.31255

StephenW

肝病学。 2020年4月4日。doi：10.1002 / hep.31255。 [Epub提前发行]
Toll样受体8激动剂GS-9688在慢性乙型肝炎的土拨鼠模型中诱导持续的疗效。
达菲斯S1，睑缘炎S1，张伯伦J1,2，郑J1，桑托斯R1，罗威W1，拉马克里希南D1，帕塔比拉曼D1，Spurlock S1,3，楚R1，康D1，米什M1，拉米雷斯R1，李L1，李B1，马S1，Hung M1，Voitenleitner C1,4，Yon C5，Suresh M5，Menne S5，Cote P5，Delaney WE 4th1，Mackman R1，Fletcher SP1。
作者信息

1个
    美国加利福尼亚州福斯特市的吉利德科学公司。
2
    Horizo​​n Therapeutics，美国加利福尼亚州南旧金山。
3
    Calithera Biosciences，美国加利福尼亚州南旧金山。
4
    瑞士Schönenbuch的Vaudaux-Eppendorf AG。
5
    美国华盛顿特区乔治敦大学医学中心。

抽象

GS-9688（selgantolimod）是toll样受体8（TLR8）的口服选择性小分子激动剂，在临床开发中用于治疗慢性乙型肝炎（CHB）。在这项研究中，我们评估了GS-9688在慢性感染土拨鼠肝炎病毒（WHV）（与乙肝病毒（HBV）密切相关的肝炎病毒）的土拨鼠中的抗病毒功效。受WHV感染的土拨鼠每周接受八次口服媒介物，分别为1 mg / kg GS-9688或3 mg / kg GS-9688。媒介物和1 mg / kg GS-9688没有抗病毒作用，而3 mg / kg GS-9688引起血清病毒载量降低> 5 log10，WHV表面抗原（WHsAg）水平降低到检测限的一半以下。处理过的土拨鼠。在这些动物中，抗病毒反应一直维持到研究结束（治疗结束后> 5个月）。 GS-9688处理可在停止治疗后维持抗病毒应答的动物体内将肝内WHV RNA和DNA含量降低> 95％，并且这些土拨鼠还开发了可检测的抗WHsAg抗体。在另一项土拨鼠研究中证实了每周口服3 mg / kg GS-9688的抗病毒功效。对GS-9688的抗病毒反应与全身性GS-9688或细胞因子水平无关，但与肝损伤生物标志物的短暂升高和外周血单核细胞（PBMC）对WHV肽的增殖反应增强有关。在治疗前进行的肝活检的转录组学分析表明，T卵泡辅助细胞（TFH）和其他各种免疫细胞亚群可能在对GS-9688的抗病毒反应中起作用。结论：临床上相关剂量的GS-9688有限的短期治疗具有良好的耐受性，并且可以在WHV感染的土拨鼠中引起持续的抗病毒反应。与对GS-9688治疗的反应相关的基线肝内转录特征的鉴定，为了解介导这种抗病毒作用的免疫机制提供了见识。

本文受版权保护。版权所有。
关键字：

乙型肝炎病毒;西尔甘托莫德TFH; TLR8；维沙托莫德

PMID：
    32246499
DOI：
    10.1002 / hep.31255

乙肝人1949

老鼠试验阶段

乙肝日记

这个要据说临床2期结束了。5%的人是表面抗原消失或者大幅度下降，是吗？还有比这个更有一样的药物吗？

newchinabok

乙肝日记 发表于 2020-4-14 06:09
这个要据说临床2期结束了。5%的人是表面抗原消失或者大幅度下降，是吗？还有比这个更有一样的药物吗？ ...

请问据说，据哪个说？

乙肝日记

回复 newchinabok 的帖子

https://m.toutiao.com/i680341025 ... tfs=MI&channel=