Shanghai Yao Yuan Biotechnology Ltd (Drug Farm) , Shanghai , China.
Zhejiang Yao Yuan Biotechnology Ltd , Jiashan , Zhejiang , China.
Hepatology. 2023 Jan 1;77(1):275-289. doi: 10.1002/hep.32614. Epub 2022 Sep 17.
In the treatment of chronic hepatitis B (CHB) infection, stimulation of innate immunity may lead to hepatitis B virus (HBV) cure. Alpha-kinase 1 (ALPK1) is a pattern recognition receptor (PRR) that activates the NF-κB pathway and stimulates innate immunity. Here we characterized the preclinical anti-HBV efficacy of DF-006, an orally active agonist of ALPK1 currently in clinical development for CHB.
In adeno-associated virus (AAV)-HBV mouse models and primary human hepatocytes (PHHs) infected with HBV, we evaluated the antiviral efficacy of DF-006. In the mouse models, DF-006 rapidly reduced serum HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen levels using doses as low as 0.08 μg/kg, 1 μg/kg, and 5 μg/kg, respectively. DF-006 in combination with the HBV nucleoside reverse transcriptase inhibitor, entecavir, further reduced HBV DNA. Antiviral efficacy in mice was associated with an increase in immune cell infiltration and decrease of hepatitis B core antigen, encapsidated pregenomic RNA, and covalently closed circular DNA in liver. At subnanomolar concentrations, DF-006 also showed anti-HBV efficacy in PHH with significant reductions of HBV DNA. Following dosing with DF-006, there was upregulation of NF-κB-targeted genes that are involved in innate immunity.
DF-006 was efficacious in mouse and PHH models of HBV without any indications of overt toxicity. In mice, DF-006 localized primarily to the liver where it potently activated innate immunity. The transcriptional response in mouse liver provides insights into mechanisms that mediate anti-HBV efficacy by DF-006.
在慢性乙型肝炎（CHB）感染的治疗中，刺激固有免疫可能导致乙型肝炎病毒（HBV）的清除。α-激酶 1（ALPK1）是一种模式识别受体（PRR），可激活 NF-κB 通路并刺激固有免疫。在此，我们对目前正在临床开发用于 CHB 的 ALPK1 口服激动剂 DF-006 的抗 HBV 前临床疗效进行了表征。
我们在腺相关病毒（AAV）-HBV 小鼠模型和感染 HBV 的原代人肝细胞（PHH）中评估了 DF-006 的抗病毒疗效。在小鼠模型中，DF-006 以低至 0.08 μg/kg、1 μg/kg 和 5 μg/kg 的剂量，迅速降低血清 HBV DNA、乙型肝炎表面抗原和乙型肝炎 e 抗原水平。DF-006 与 HBV 核苷逆转录酶抑制剂恩替卡韦联合使用，进一步降低 HBV DNA。在小鼠中观察到的抗病毒疗效与免疫细胞浸润增加以及肝脏中乙型肝炎核心抗原、包裹前基因组 RNA 和共价闭合环状 DNA 减少有关。在 SUBnM 浓度下，DF-006 对 PHH 中的 HBV 也具有抗病毒作用，HBV DNA 显著减少。DF-006 给药后，NF-κB 靶向基因的表达上调，这些基因参与固有免疫。
DF-006 在 HBV 的小鼠和 PHH 模型中具有疗效，且没有明显的毒性迹象。在小鼠中，DF-006 主要定位于肝脏，在肝脏中能强有力地激活固有免疫。小鼠肝脏中的转录反应为 DF-006 介导抗 HBV 疗效的机制提供了见解。
