In vitro characterization of GS-9620, a toll-like receptor 7 agonist (P4441)

Abstract

Abstract Efficient innate and adaptive immunity is necessary for initial containment and subsequent clearance of viral infections, including hepatitis B and C viruses. A feature of an effective anti-viral immune response is the interaction of single stranded viral RNA with toll-like receptor 7 and activation of plasmacytoid dendritic cells and B lymphocytes. In this study, the novel toll-like receptor 7 agonist GS 9620 was characterized in regards to its toll-like receptor selectivity and its ability to activate innate and adaptive immune responses in vitro. GS 9620 selectively activated human toll-like receptor 7 over other toll-like receptors and induced several cytokines and chemokines in a concentration dependent manner. In particular, GS-9620 was able to induce secretion of interferon-alpha at 55-fold lower concentrations compared to those that induce tumor necrosis factor in human PBMCs and isolated plasmacytoid dendritic cell cultures. We also detected GS-9620-dependent induction of interferon stimulated gene expression in PBMCs. Moreover, GS-9620 transiently induced the expression of the activation markers CD25 and CD69 in both CD3+CD4+ and CD3+CD8+ T lymphocyte subsets as well as up-regulated expression of CD69 and the co-stimulatory molecule CD86 on CD20+ B lymphocytes. In conclusion, GS-9620 is a potent and selective toll-like receptor 7 agonist that activates innate and adaptive antiviral immune responses which is currently being evaluated in human clinical trials.