1114 Anti-Viral Efficacy and Induction of an Antibody Response Against Surface Antigen With the Tlr7 Agonist Gs-9620 in the Woodchuck Model of Chronic HBV Infection

Menne, Stephan; Tennant, Bud C.; Liu, K.H.; Ascenzi, Mary; Baldwin, Betty H.; Bellezza, Christine A.; Côté, Paul J.; Zheng, Xiaojing; Wolfgang, Grushenka H.I.; Turnas, D.

doi:10.1016/s0168-8278(11)61116-1

Cited by 28 publications

(21 citation statements)

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“…The therapeutic benefit of TLR7 stimulation by oral GS-9620 in animal models of chronic HBV infection has been shown in both chimpanzees infected with HBV and the woodchuck hepatitis virus model (Menne et al, 2011;Lanford et al, 2013). Importantly, in uninfected and chronic HBV-infected chimpanzees, GS-9620 induced ISGs in the liver and/or in PBMC with no detectable increase in serum levels of IFN-a at low doses.…”

Section: Discussionmentioning

confidence: 99%

“…The therapeutic benefit of TLR7 stimulation by oral GS-9620 in animal models of chronic HBV infection has been shown in both chimpanzees infected with HBV and the woodchuck hepatitis virus model. In both models, oral administration of GS-9620 reduced viremia and induced an antiviral immune response, and in woodchucks, GS-9620 induced an antibody response to viral surface antigen with subsequent clearance of viral S-antigen (Menne et al, 2011;Lanford et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic and Pharmacodynamic Properties of GS-9620, a Novel Toll-Like Receptor 7 Agonist, Demonstrate Interferon-Stimulated Gene Induction without Detectable Serum Interferon at Low Oral Doses

Fosdick

Zheng

Pflanz

et al. 2013

J Pharmacol Exp Ther

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GS -9620 [8-(3-(pyrrolidin-1-ylmethyl)benzyl)-4-amino-2-butoxy-7,8-dihydropteridin-6(5H)-one] is a potent, orally bioavailable small-molecule agonist of Toll-like receptor 7 (TLR7) developed for finite treatment of chronic hepatitis B viral (HBV) infection, with the goal of inducing a liver-targeted antiviral effect without inducing the adverse effects associated with current systemic interferon-a (IFN-a) therapies. We characterized the pharmacodynamic response of GS-9620 in CD-1 mice and cynomolgus monkeys following intravenous or oral administration and showed that GS-9620 induces the production of select chemokines and cytokines, including IFN-a and interferon-stimulated genes (ISGs). It is noteworthy that we also demonstrated that, in animals and healthy human volunteers, oral administration of GS-9620 can induce a type I interferon-dependent antiviral innate immune response, as measured by whole-blood mRNA of the ISGs 2959-oligoadenylate synthetase 1 (OAS1) and myxovirus resistance 1 (MX1), without the induction of detectable systemic IFN-a, i.e., a presystemic response. Additionally, presystemic induction of hepatic OAS1 and MX1 mRNA was observed in CD-1 mice in the absence of detectable systemic IFN-a. We propose that the mechanism of this presystemic response is likely its high intestinal absorption, which facilitates localized activation of TLR7, probably in plasmacytoid dendritic cells at the level of gut-associated lymphoid tissue and/or the liver. This localized response is further supported by data that indicate only minimal contributions of systemic immune stimulation to the overall pharmacodynamic response to orally administered GS-9620. These data demonstrate that GS-9620 can induce an antiviral innate immune response without inducing a systemic IFN-a response and thus suggest the therapeutic potential of this approach in the treatment of chronic HBV infection.

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Section: Discussionmentioning

confidence: 99%

“…The therapeutic benefit of TLR7 stimulation by oral GS-9620 in animal models of chronic HBV infection has been shown in both chimpanzees infected with HBV and the woodchuck hepatitis virus model. In both models, oral administration of GS-9620 reduced viremia and induced an antiviral immune response, and in woodchucks, GS-9620 induced an antibody response to viral surface antigen with subsequent clearance of viral S-antigen (Menne et al, 2011;Lanford et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Properties of GS-9620, a Novel Toll-Like Receptor 7 Agonist, Demonstrate Interferon-Stimulated Gene Induction without Detectable Serum Interferon at Low Oral Doses

Fosdick

Zheng

Pflanz

et al. 2013

J Pharmacol Exp Ther

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“…Interestingly, a 4-week treatment with GS-9620 resulted in a sustained, marked reduction in serum WHV DNA and WHsAg levels and in the induction of anti-WHs antibody responses as well as a markedly decreased incidence of hepatocellular carcinoma in chronic WHV-infected woodchucks. 79 Furthermore, GS-9620 induced an increase in serum IFN-a in a dose-dependent manner and triggered ISG expression in PBMCs and the liver in chimpanzees. Short-term oral administration of GS-9620 resulted in a long-term suppression of serum and liver HBV DNA, as well as a reduction in serum levels of HBsAg and HBeAg in 3 chronically HBV-infected chimpanzees.…”

Section: Using Tlr Agonists For Immunotherapy In Chronic Hbv Infectionmentioning

confidence: 96%

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Zhang

Yang

et al. 2014

Cell Mol Immunol

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It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus (HBV) infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons (IFNs) and pro-inflammatory cytokines. Experimental results from in vitro and in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T-and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.

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“…In addition, exogenous TLR-mediated activation can suppress HBV replication in HBV-transgenic mice ) and in HBV-transfected HepG2 and Huh7 cells (Guo et al 2009). Production of intrahepatic antiviral cytokines (IFN-a, IFNg), through oral administration of TLR agonists, has also shown efficacy in HBV-infected woodchucks (Menne et al 2011) and chimpanzees (Lanford et al 2013). Thus, to maximize intrahepatic innate immune function, strategies to specifically deliver antiviral cytokines to the infected liver or to target activation of intrahepatic Kupffer and NK cells have been proposed.…”

Section: Immunological-based Treatments Of Chronic Hbv Infectionmentioning

confidence: 99%

Immune Response in Hepatitis B Virus Infection

Tan

Koh

Bertoletti

2015

Cold Spring Harb Perspect Med

102

104

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Hepatitis B virus (HBV) can replicate within hepatocytes without causing direct cell damage. The host immune response is, therefore, not only essential to control the spread of virus infection, but it is also responsible for the inflammatory events causing liver pathologies. In this review, we discuss how HBV deals with host immunity and how we can harness it to achieve virus control and suppress liver damage.

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1114 Anti-Viral Efficacy and Induction of an Antibody Response Against Surface Antigen With the Tlr7 Agonist Gs-9620 in the Woodchuck Model of Chronic HBV Infection

Cited by 28 publications

References 0 publications

Pharmacokinetic and Pharmacodynamic Properties of GS-9620, a Novel Toll-Like Receptor 7 Agonist, Demonstrate Interferon-Stimulated Gene Induction without Detectable Serum Interferon at Low Oral Doses

Pharmacokinetic and Pharmacodynamic Properties of GS-9620, a Novel Toll-Like Receptor 7 Agonist, Demonstrate Interferon-Stimulated Gene Induction without Detectable Serum Interferon at Low Oral Doses

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Immune Response in Hepatitis B Virus Infection

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