Therapeutic Potential of TLR8 Agonist GS-9688 (Selgantolimod) in Chronic Hepatitis B: Remodeling of Antiviral and Regulatory Mediators.
Therapeutic Potential of TLR8 Agonist GS-9688 (Selgantolimod) in Chronic Hepatitis B: Remodeling of Antiviral and Regulatory Mediators.
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TLR8激动剂GS-9688（Selgantolimod）在慢性肝炎B中的治疗潜力：抗病毒和调节介质的重塑。
DOI：
10.1002/hep.31695
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Pallett LJ
中科院分区：
文献类型：
--
作者：
Amin OE;Colbeck EJ;Daffis S;Khan S;Ramakrishnan D;Pattabiraman D;Chu R;Micolochick Steuer H;Lehar S;Peiser L;Palazzo A;Frey C;Davies J;Javanbakht H;Rosenberg WMC;Fletcher SP;Maini MK;Pallett LJ
GS-9688（selgantolimod）是一种Toll样受体8激动剂，临床开发用于治疗慢性B肝炎（CHB）。先前已在HBV感染的肝细胞中进行了体外评价，并在CHB土拨鼠模型中进行了体内评价。在此，我们评估了GS-9688促进有助于病毒控制的应答和调节调节介质的潜力。我们表征了GS-9688对健康对照和CHB患者外周血单核细胞中免疫细胞亚群的体外影响。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，在健康对照和CHB患者中诱导相当的细胞因子谱。GS-9688增加了活化的自然杀伤（NK）细胞、粘膜相关不变T细胞、CD 4+滤泡辅助T细胞的频率，在约50%的患者中，增加了表达干扰素-γ的HBV特异性CD 8 + T细胞的频率。此外，GS-9688体外刺激诱导NK细胞表达干扰素-γ和TNF-α，并促进肝细胞溶解。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刺激降低了CD 4+调节性T细胞和单核细胞髓源性抑制细胞（MDSC）的频率。剩余的MDSC表达更高水平的负性免疫调节剂，半乳糖凝集素-9和程序性死亡配体1。相反，GS-9688诱导免疫调节性TNF-相关凋亡诱导配体+ NK细胞的扩增和β-内酰胺酶-I+多形核MDSC的脱粒。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CD 8 + T细胞、CD 4+滤泡辅助T细胞、NK细胞和粘膜相关不变T细胞）激活抗病毒效应子功能。虽然降低了某些免疫调节亚群的频率，但它增强了其他亚群的免疫抑制潜力，突出了潜在的生物标志物和免疫靶点，以优化GS-9688的抗病毒疗效。
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.
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影响因子：
5.5
作者：
Dang Y;Rutnam ZJ;Dietsch G;Lu H;Yang Y;Hershberg R;Disis ML
通讯作者：
Disis ML
GS-9620是Toll样受体-7的口服激动剂，可长期抑制慢性感染的黑猩猩的丙型肝炎病毒。
影响因子：
29.4
作者：
Lanford RE;Guerra B;Chavez D;Giavedoni L;Hodara VL;Brasky KM;Fosdick A;Frey CR;Zheng J;Wolfgang G;Halcomb RL;Tumas DB
通讯作者：
Tumas DB
影响因子：
32.4
作者：
Choi YS;Kageyama R;Eto D;Escobar TC;Johnston RJ;Monticelli L;Lao C;Crotty S
通讯作者：
Crotty S
影响因子：
5.9
作者：
Levrero, Massimo;Testoni, Barbara;Zoulim, Fabien
通讯作者：
Zoulim, Fabien
影响因子：
2.5
作者：
Agarwal, K.;Ahn, S. H.;Nguyen, M. H.
通讯作者：
Nguyen, M. H.