Abstract
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-α (IFN-α) 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-α 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 2′5′-oligoadenylate synthetase 1 (OAS1) and myxovirus resistance 1 (MX1), without the induction of detectable systemic IFN-α, 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-α. 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-α response and thus suggest the therapeutic potential of this approach in the treatment of chronic HBV infection.
Footnotes
- Received July 16, 2013.
- Accepted October 16, 2013.
This work was supported by Gilead Sciences, Inc., Foster City, CA.
This work was presented previously, in part, at two meetings: Tumas D, Zheng X, Lu B, Rhodes G, Duatschek P, Hesselgesser J, Frey C, Henne I, Fosdick A, Halcomb R, and Wolfgang G (2011) Preclinical characterization of GS-9620, a potent and selective oral TLR7 agonist (Abstract 1776). 46th Annual Meeting of the European Association for the Study of the Liver; 2011 March 30–April 3; Berlin, Germany; and Tumas D, Fosdick A, Zheng X, Lanford R, Hesselgesser J, Frey C, Wolfgang G, Halcomb R, and Lopatin U (2012) GS-9620, induces a presystemic innate immune response in the absence of serum interferon or adverse effects in both non-clinical species and humans (Abstract 18640). 47th Annual Meeting of the European Association for the Study of the Liver; 2012 April 18–22; Barcelona, Spain.
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- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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