Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, United Kingdom.
Gilead Sciences Inc., Foster City, CA.
Hepatology. 2021 Jul;74(1):55-71. doi: 10.1002/hep.31695. Epub 2021 Jun 20.
GS-9688 (selgantolimod) is a toll-like receptor 8 agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS-9688 has previously been evaluated in vitro in HBV-infected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GS-9688 to boost responses contributing to viral control and to modulate regulatory mediators.
We characterized the effect of GS-9688 on immune cell subsets in vitro in peripheral blood mononuclear cells of healthy controls and patients with CHB. GS-9688 activated dendritic cells and mononuclear phagocytes to produce IL-12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and patients with CHB. GS-9688 increased the frequency of activated natural killer (NK) cells, mucosal-associated invariant T cells, CD4 follicular helper T cells, and, in about 50% of patients, HBV-specific CD8 T cells expressing interferon-γ. Moreover, in vitro stimulation with GS-9688 induced NK-cell expression of interferon-γ and TNF-α, and promoted hepatocyte lysis. We also assessed whether GS-9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GS-9688 reduced the frequency of CD4 regulatory T cells and monocytic myeloid-derived suppressor cells (MDSCs). Residual MDSCs expressed higher levels of negative immune regulators, galectin-9 and programmed death-ligand 1. Conversely, GS-9688 induced an expansion of immunoregulatory TNF-related apoptosis-inducing ligand NK cells and degranulation of arginase-I polymorphonuclear MDSCs.
GS-9688 induces cytokines in human peripheral blood mononuclear cells that are able to activate antiviral effector function by multiple immune mediators (HBV-specific CD8 T cells, CD4 follicular helper T cells, NK cells, and mucosal-associated invariant T cells). Although reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimize the antiviral efficacy of GS-9688.
GS-9688（selgantolimod）是一种临床开发用于治疗慢性乙型肝炎（CHB）的 Toll 样受体 8 激动剂。GS-9688 的抗病毒活性已在体外感染乙型肝炎病毒的肝细胞和体内土拨鼠 CHB 模型中进行了评估。在这里，我们评估了 GS-9688 增强有助于病毒控制的反应和调节调节介质的潜力。
我们在健康对照者和 CHB 患者的外周血单核细胞中体外研究了 GS-9688 对免疫细胞亚群的影响。GS-9688 激活树突状细胞和单核吞噬细胞产生 IL-12 和其他免疫调节介质，在健康对照者和 CHB 患者中诱导类似的细胞因子谱。GS-9688 增加了活化自然杀伤（NK）细胞、黏膜相关不变 T 细胞、CD4 滤泡辅助 T 细胞的频率，并且在大约 50%的患者中，HBV 特异性 CD8 T 细胞表达干扰素-γ。此外，GS-9688 体外刺激诱导 NK 细胞表达干扰素-γ和 TNF-α，并促进肝细胞裂解。我们还评估了 GS-9688 是否抑制可能增强抗病毒疗效的免疫抑制细胞亚群。GS-9688 刺激减少了 CD4 调节性 T 细胞和单核细胞髓样来源的抑制细胞（MDSCs）的频率。残留的 MDSCs 表达更高水平的负免疫调节剂半乳糖凝集素-9 和程序性死亡配体 1。相反，GS-9688 诱导免疫调节 TNF 相关凋亡诱导配体 NK 细胞的扩增和精氨酸酶-I 多形核 MDSCs 的脱颗粒。
GS-9688 诱导人外周血单核细胞中的细胞因子，这些细胞因子能够通过多种免疫介质（HBV 特异性 CD8 T 细胞、CD4 滤泡辅助 T 细胞、NK 细胞和黏膜相关不变 T 细胞）激活抗病毒效应功能。尽管减少了一些免疫调节亚群的频率，但它增强了其他免疫抑制亚群的免疫抑制潜力，突出了潜在的生物标志物和免疫治疗靶点，以优化 GS-9688 的抗病毒疗效。
