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FRI-143
ANTIVIRAL EFFICACY AND HOST IMMUNE RESPONSE INDUCTION
WITH SB 9200, AN ORAL PRODRUG OF THE DINUCLEOTIDE SB
9000, IN COMBINATION WITH ENTECAVIR IN THE WOODCHUCK
MODEL OF CHRONIC HEPATITIS B
K. Korolowicz1, M. Balarezo1, R. Iyer2, S. Padmanabhan2, D. Cleary2,
R. Gimi2, A. Sheri2, M. Suresh1, C. Yon1, R. Tucker3, N. Afdhal2,
S. Menne1. 1Microbiology and Immunology, Georgetown University,
Washington; 2Spring Bank Pharmaceuticals Inc, Milford; 3Comparative
Medicine, Georgetown University, Washington, United States
E-mail: [email protected]
Background and Aims: SB 9200 is a small orally bioavailable
dinucleotide that activates the cellular viral sensors RIG-I and NOD2
causing the induction of IFN signaling cascade for antiviral defense. In
preclinical studies, SB 9200 has shown to be a potent anti-HBV agent.
In WHV-infected woodchucks, SB 9200 monotherapy resulted in
potent antiviral activity (Menne, et al., EASL 2015). The aim of this
study was to evaluate the overall antiviral response in woodchucks
upon induction of innate immune response first with SB 9200
followed by Entecavir (ETV) treatment versus reduction of viral
burden with ETV treatment followed by immune modulation with SB
9200.
Methods: Two groups of five woodchuckswere treated orally with SB
9200 (30 mg/kg/day) and ETV (0.5 mg/kg/day). Group 1 received ETV
for 4 weeks followed by SB 9200 for 12 weeks. Group 2 received SB
9200 for 12 weeks followed by ETV for 4 weeks. Both groups were
monitored for 8 weeks post-treatment.
Results: At the end of treatment in Group 2, average reductions of
6.4 log10 in serum WHV DNA and 3.3 log10 in WHV surface antigen
(WHsAg) were observed whereas in Group 1, average reductions of
4.2 log10 and 1.1 log 10 in serum WHV DNA and WHsAg were seen
compared to pre-treatment levels. Both treatment groups
demonstrated significant reductions of WHV DNA replicative
intermediates, cccDNA, and RNA in Group 2 (76%, 49%, and 51%)
and Group 1 (57%, 39%, and 41%). Following cessation of treatment
and the 8-week follow-up period, recrudescence of WHV replication
was observed in Group 1, whereas recrudescence in Group 2 was
much delayed with viremia and antigenemia staying at 1.7 and
0.7 log10 below pre-treatment levels. Overall, both treatments
reduced hepatic WHV antigen expression and slowed liver disease
progression. Seroconversion to anti-WHs antibodywas not observed.
The antiviral effects were also associated with the induction of IFN-α,
IFN-β, OAS-1, CXCL10, ISG15, and IL-6 in blood and liver, which were
more pronounced in Group 2 compared to Group 1.
Conclusions: Induction of host immune response by pretreatment
with SB 9200 followed by ETV in woodchucks resulted in significant
declines in viral DNA, RNA, and antigens that was superior to that
seen using the strategy of viral reduction with ETV followed by
immune modulation. These data support the planned Phase II clinical
trial of SB 9200 alone and in combination with a nucleoside in the
treatment of chronic HBV.
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发表于 2016-4-1 17:20