GS-9620, a potent and orally available TLR7 agonist, is the front runner of PRR agonists under development for treatment of chronic hepatitis B. Its great therapeutic potential has been demonstrated in preclinical studies in woodchucks infected with woodchuck hepatitis virus (WHV) and HBV-infected chimpanzees. Specifically, treatment of woodchucks chronically infected by WHV with varying dose frequencies of GS-9620 for 4–8 weeks resulted in a greater than 6 log reduction of viral load. Intriguingly, while 15 out of 19 animals had dramatic viral load reductions during treatment, the suppressive effect on viral load was sustained in 12 of these 15 animals, and 13 of the 15 sustained WHsAg loss after cessation of treatment. Moreover, for those with sustained WHsAg loss, 8 of 13 developed an antibody against the surface antigen (Menne et al., 2015). This result is in marked contrast to treatment with nucleoside analogs and IFN-α, which rarely resulted in WHsAg seroconversion (Fletcher et al., 2012 and Menne and Cote, 2007). Mechanism of action studies suggested that consistent with activation of TLR-7 signaling, the antiviral response induced by GS-9620 is likely mediated by both the cytolytic activity of CD8+ T cells and/or NK cells, and type I/II IFN-mediated non-cytolytic activity, as well as activation of B cells, in the liver microenvironment.
In a chimpanzee study, GS-9620 treatment of three HBV chronically infected animals for 8 weeks also reduced viral load by more than 2 logs and resulted in greater than a 50% reduction in HBsAg and HBeAg serum levels. While reduction of viral load by 1 log persisted, no HBsAg seroconversion occurred in any of the treated animals (Lanford et al., 2013). Although IFN-α was transiently induced, the suppression of HBV/HBsAg coincided with NK/T cell activation. Hence, it is most likely that the TLR-7 therapeutic effect relies on not only induction of IFNs, but also activation of other branches of intrahepatic innate immune responses.
Pharmacokinetic and pharmacodynamic studies in healthy volunteers suggested that at low oral doses, GS-9620 induces a type I interferon-dependent antiviral innate immune response without the induction of systemic IFN-α. This presystemic response is likely due to its high intestinal absorption and activation of TLR7 locally via oral administration ( Fosdick et al., 2014). In two phase 1b studies reported recently, one or two low doses of GS-9620 administered once a week were safe and well tolerated ( Gane et al., 2015). However, phase 1 studies did not show evidence of clinical efficacy of GS-9620 in terms of HBV DNA decline, HBsAg reduction ( Gane et al., 2015) or decrease in HCV RNA ( Lawitz et al., 2014). Further clinical investigations are certainly warranted to optimize the dosage and treatment schedules.作者: newchinabok 时间: 2015-10-17 10:24
Stimulator of interferon genes (STING) is the adaptor protein of multiple cytoplasmic DNA receptors and a PRR recognizing the bacterial second messengers, cyclic di-adenosine monophosphate (c-di-AMP) and cyclic di-guanosine monophosphate (c-di-GMP) (Burdette and Vance, 2013). It was discovered recently that cytoplasmic DNA activates cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) to produce cGAMP, which subsequently binds to STING and induces IFNs and other cytokines (Gao et al., 2013 and Ishikawa and Barber, 2008). The fact that STING can be activated by cyclic di-nucleotides implies that like TLR7 and TLR8, STING might be activated by other small molecules and thus be a potential target for pharmacological activation of innate immune responses, as well as priming of an adaptive immune response.
Indeed, we recently showed that 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a mouse STING agonist, induced a type I-IFN-dominant cytokine response in macrophages, which potently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Moreover, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of HBV-hydrodynamically injected mice. Our study thus provides proof of concept that activation of the STING pathway induces a potent innate antiviral response, and that the development of small-molecule human STING agonists as immunotherapeutic agents for the treatment of chronic hepatitis B is warranted (Guo et al., 2015).
Many PRR agonists have thus far been tested in animal models or in clinical studies for their effects on chronic viral infections of the liver, including hepatitis B. Although promising results have been obtained, the search for the proper agonists that fine-tune host immune responses and cure chronic HBV infection is still under way. In addition, there are many studies reporting HBV evasion and antagonization of innate immune pathways under certain experimental conditions (reviewed in (Chang et al., 2012)). Further investigation is required to re-examine such phenomena in the context of viral replication and in human hepatocytes during natural infection. If confirmed, pharmacological interruption of HBV antagonism of host innate immune responses should be an ideal therapeutic strategy to restore innate, and possibly also adaptive immunity to HBV infection作者: zgct 时间: 2015-10-17 19:11