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428
Evaluating the Translational Value of the
Woodchuck Model of Chronic Hepatitis B with
the Toll-like 7 Receptor Agonist Vesatolimod
Scott Balsitis1, Sandra Spurlock1, Divya Pattabiraman1, Ruth
Chu1, Stephane Daffis2, Jim Zheng1, Bei Lei1, Sarina Ma1,
William Rowe1, Christian Voitenleitner1, Magdeleine Hung1,
Paul J. Cote3, William E. Delaney1 and Simon Fletcher1, (1)
Gilead Sciences, Inc., (2)Virology, Gilead Sciences, Inc., (3)
Georgetown University Medical Center
Background: Vesatolimod (GS-9620) is a small molecule
agonist of toll-like receptor 7 (TLR7) which can also activate
TLR8 at high concentrations. Weekly dosing of 5 mg/kg
vesatolimod for 8 weeks in the woodchuck model of chronic
hepatitis B (CHB) induced profound antiviral effects and
increased interferon-stimulated gene (ISG) mRNA levels in
the blood. In contrast, 4 mg vesatolimod dosed weekly in
CHB patients for 12 weeks upregulated the same ISGs but
had no antiviral effect. Here we performed studies to address
this discrepancy in preclinical vs. clinical response. Methods:
Vesatolimod was evaluated in HEK293 cells transiently
expressing human or woodchuck TLR7 or TLR8 and an NF-
κB-driven reporter. Naïve (uninfected) woodchucks (n=4/
group) were administered a single oral dose of 0.3, 1, 2.5 or
5 mg/kg vesatolimod and serum IFN-α (bioassay), serum IL-
12p40 (ELISA) and whole blood interferon-stimulated gene
(ISG) mRNA levels (qRT-PCR) measured at 4-48 hours postdose.
Chronically infected woodchucks (n=6-9/group) were
orally administered vehicle, 0.3, 1, 2.5 or 5 mg/kg vesatolimod
weekly for 4-14 weeks and serum WHV DNA and WHsAg
were measured. Results: Vesatolimod displayed >15-fold
selectivity for human TLR7 over TLR8, but only 4-fold selectivity
for woodchuck TLR7 over TLR8. In naïve woodchucks, 0.3
mg/kg vesatolimod induced ISG mRNAs but did not increase
serum IFN-α or IL-12p40 levels. Serum IFN-α levels in naïve
woodchucks were elevated by 1 mg/kg vesatolimod and
strongly induced by doses ≥2.5 mg/kg. Serum IL-12p40 levels
were also increased by the higher doses of vesatolimod.
Administration of 0.3 mg/kg vesatolimod for 6 weeks had no
antiviral activity in chronically infected woodchucks, and 14
weeks of 1 mg/kg induced an antiviral response in only 14%
animals. Treatment with 2.5 mg/kg vesatolimod for 14 weeks
induced an antiviral response in 28% of animals, and short
duration treatment (4 weeks) with 5 mg/kg induced an antiviral
response in 33% of animals. Conclusion: Vesatolimod had
no antiviral activity in woodchucks at a dose (0.3 mg/kg) that
induced comparable pharmacodynamic responses to those
observed in CHB patients. Higher doses induced an antiviral
response in a subset of animals, but substantially increased
serum IFN-α and IL-12p40. Collectively, our data suggest
that the antiviral response to vesatolimod in the woodchuck
model may be due to stronger activation of TLR7 than was
achieved in CHB patients, and potentially also activation of
TLR8.
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发表于 2018-10-20 12:53