Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B
Autor: | Ricardo Ramirez, Li Li, William E. Delaney, Stephan Menne, Sarina Ma, Changsuek Yon, Don Kang, Jason Chamberlain, Christian Voitenleitner, William Rowe, Ruth Chu, Dhivya Ramakrishnan, Magdeleine Hung, Manasa Suresh, Divya Pattabiraman, Stephane Daffis, Paul J. Cote, Rex Santos, Bei Li, Simon P. Fletcher, Scott Balsitis, Sandra Spurlock, Mish Michael R, Jim Zheng, Richard L. Mackman |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Agonist medicine.drug_class Viral Hepatitis viruses Pharmacology Virus Replication medicine.disease_cause Antiviral Agents 03 medical and health sciences Hepatitis B Chronic 0302 clinical medicine Immune system Antigen medicine Animals Hepatitis B Virus Woodchuck Humans Hepatitis Antibodies Hepatitis B virus Hepatology biology business.industry Woodchuck hepatitis virus Hepatitis Antigens Original Articles biochemical phenomena metabolism and nutrition Hepatitis B biology.organism_classification medicine.disease digestive system diseases Disease Models Animal Pyrimidines 030104 developmental biology Toll-Like Receptor 8 Marmota DNA Viral biology.protein Original Article 030211 gastroenterology & hepatology Antibody Hexanols business Viral load |
Zdroj: | Hepatology (Baltimore, Md.) |
ISSN: | 1527-3350 0270-9139 |
Popis: | Background and aims GS-9688 (selgantolimod) is an oral selective small molecule agonist of toll-like receptor 8 in clinical development for the treatment of chronic hepatitis B. 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. Approach and results 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 to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells and various other immune cell subsets may play a role in the antiviral response to GS-9688. Conclusions 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. |
Databáze: | OpenAIRE |
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