title: Antiviral Efficacy and Host Innate Immunity Associated with SB 9200 Treatment in the Woodchuck Model of Chronic Hepatitis B.
abstract: SB 9200, an oral prodrug of the dinucleotide SB 9000, is being developed for the treatment of chronic hepatitis B virus (HBV) infection and represents a novel class of antivirals. SB 9200 is thought to activate the viral sensor proteins, retinoic acid-inducible gene 1 (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) resulting in interferon (IFN) mediated antiviral immune responses in virus-infected cells. Additionally, the binding of SB 9200 to these sensor proteins could also sterically block the ability of the viral polymerase to access pre-genomic RNA for nucleic acid synthesis. The immune stimulating and direct antiviral properties of SB 9200 were evaluated in woodchucks chronically infected with woodchuck hepatitis virus (WHV) by daily, oral dosing at 15 and 30 mg/kg for 12 weeks. Prolonged treatment resulted in 2.2 and 3.7 log10 reductions in serum WHV DNA and in 0.5 and 1.6 log10 declines in serum WHV surface antigen from pretreatment level with the lower or higher dose of SB 9200, respectively. SB 9200 treatment also resulted in lower hepatic levels of WHV nucleic acids and antigen and reduced liver inflammation. Following treatment cessation, recrudescence of viral replication was observed but with dose-dependent delays in viral relapse. The antiviral effects were associated with dose-dependent and long-lasting induction of IFN-α, IFN-β and IFN-stimulated genes in blood and liver, which correlated with the prolonged activation of the RIG-I/NOD2 pathway and hepatic presence of elevated RIG-I protein levels. These results suggest that in addition to a direct antiviral activity, SB 9200 induces antiviral immunity during chronic hepadnaviral infection via activation of the viral sensor pathway.
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, 20057, United States of America.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Korolowicz
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Suite S-7, 113 Cedar Street, Milford, MA, 01757, United States of America.
authors.forename: Radhakrishnan P
authors.initials: RP
authors.lastname: Iyer
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, 20057, United States of America.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Czerwinski
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, 20057, United States of America.
authors.forename: Manasa
authors.initials: M
authors.lastname: Suresh
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, 20057, United States of America.
authors.forename: Junming
authors.initials: J
authors.lastname: Yang
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Suite S-7, 113 Cedar Street, Milford, MA, 01757, United States of America.
authors.forename: Seetharamaiyer
authors.initials: S
authors.lastname: Padmanabhan
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Suite S-7, 113 Cedar Street, Milford, MA, 01757, United States of America.
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Sheri
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Suite S-7, 113 Cedar Street, Milford, MA, 01757, United States of America.
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Pandey
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Suite S-7, 113 Cedar Street, Milford, MA, 01757, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Skell
authors.affiliation: Spring Bank Pharmaceuticals, Inc., Suite S-7, 113 Cedar Street, Milford, MA, 01757, United States of America.
authors.forename: Judith K
authors.initials: JK
authors.lastname: Marquis
authors.affiliation: Department of Pathology, Georgetown University Medical Center, Washington, DC, 20057, United States of America.
authors.forename: Bhaskar V
authors.initials: BV
authors.lastname: Kallakury
authors.affiliation: Department of Comparative Medicine, Georgetown University Medical Center, Washington, DC, 20057, United States of America.
authors.forename: Robin D
authors.initials: RD
authors.lastname: Tucker
authors.affiliation: Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, 20057, United States of America.
authors.forename: Stephan
authors.initials: S
authors.lastname: Menne
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D017919:Hepatitis B Virus, Woodchuck / Q000187:drug effects / Q000472:pathogenicity; D006515:Hepatitis B virus / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D016898:Interferon-alpha / Q000097:blood; D016899:Interferon-beta / Q000097:blood; D008099:Liver / Q000378:metabolism; D008392:Marmota / Q000276:immunology / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D016899:Interferon-beta