دورية أكاديمية
أعرض في EDS

Therapeutic Potential of TLR8 Agonist GS-9688 (Selgantolimod) in Chronic Hepatitis B: Remodeling of Antiviral and Regulatory Mediators.

التفاصيل البيبلوغرافية
العنوان: Therapeutic Potential of TLR8 Agonist GS-9688 (Selgantolimod) in Chronic Hepatitis B: Remodeling of Antiviral and Regulatory Mediators.
المؤلفون: Amin OE; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, United Kingdom., Colbeck EJ; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, United Kingdom., Daffis S; Gilead Sciences Inc., Foster City, CA., Khan S; Gilead Sciences Inc., Foster City, CA., Ramakrishnan D; Gilead Sciences Inc., Foster City, CA., Pattabiraman D; Gilead Sciences Inc., Foster City, CA., Chu R; Gilead Sciences Inc., Foster City, CA., Micolochick Steuer H; Gilead Sciences Inc., Foster City, CA., Lehar S; Gilead Sciences Inc., Foster City, CA., Peiser L; Gilead Sciences Inc., Foster City, CA., Palazzo A; Gilead Sciences Inc., Foster City, CA., Frey C; Gilead Sciences Inc., Foster City, CA., Davies J; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, United Kingdom., Javanbakht H; Gilead Sciences Inc., Foster City, CA., Rosenberg WMC; Institute for Liver and Digestive Health, University College London, London, United Kingdom., Fletcher SP; Gilead Sciences Inc., Foster City, CA., Maini MK; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, United Kingdom., Pallett LJ; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, United Kingdom.
المصدر: Hepatology (Baltimore, Md.) [Hepatology] 2021 Jul; Vol. 74 (1), pp. 55-71. Date of Electronic Publication: 2021 Jun 20.
نوع المنشور: Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 8302946 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1527-3350 (Electronic) Linking ISSN: 02709139 NLM ISO Abbreviation: Hepatology Subsets: MEDLINE
أسماء مطبوعة: Publication: 2023- : [Philadelphia] : Wolters Kluwer Health, Inc.
Original Publication: Baltimore, MD : Williams & Wilkins, [c1981]-
مواضيع طبية MeSH: Antiviral Agents/*pharmacology , Hepatitis B, Chronic/*drug therapy , Hexanols/*pharmacology , Pyrimidines/*pharmacology , Toll-Like Receptor 8/*antagonists & inhibitors, Adult ; Aged ; Animals ; Antiviral Agents/therapeutic use ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; Cohort Studies ; Disease Models, Animal ; Female ; Healthy Volunteers ; Hep G2 Cells ; Hepatitis B, Chronic/immunology ; Hepatitis B, Chronic/virology ; Hexanols/therapeutic use ; Host-Pathogen Interactions/drug effects ; Host-Pathogen Interactions/immunology ; Humans ; Killer Cells, Natural/drug effects ; Killer Cells, Natural/immunology ; Leukocytes, Mononuclear ; Male ; Marmota ; Middle Aged ; Primary Cell Culture ; Pyrimidines/therapeutic use ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; Toll-Like Receptor 8/metabolism ; Young Adult
مستخلص: Background and Aims: 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.
Approach and Results: 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.
Conclusions: 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.
(© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
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معلومات مُعتمدة: 26603 United Kingdom CRUK_ Cancer Research UK
المشرفين على المادة: 0 (Antiviral Agents)
0 (Hexanols)
0 (Pyrimidines)
0 (TLR8 protein, human)
0 (Toll-Like Receptor 8)
RM4GJT3SMQ (selgantolimod)
تواريخ الأحداث: Date Created: 20201228 Date Completed: 20220104 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC8436741
DOI: 10.1002/hep.31695
PMID: 33368377
قاعدة البيانات: MEDLINE
الوصف
تدمد:1527-3350
DOI:10.1002/hep.31695