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本帖最后由 StephenW 于 2018-4-18 19:46 编辑
EASL 2018 SAT-435
Preclinical mechanistic and efficacy evaluation of a novel small
molecule TLR7 agonist RO7020531 for the treatment of chronic
hepatitis B
L. Dai1, X. Yu1, Y. Yu1, L. Gu1, J. Zhao1, L. Zhu1, G. Ottaviani2, H. Yun1,
M. Ait-Goughoulte2, M. Ilnicka2, J. Xie1, L. Wang2, A. Feng1, J. Young2,
L. Gao1. 1Roche Innovation Center Shanghai; 2Roche Innovation
Center Basel
Email: [email protected]
Background and Aims: Chronic hepatitis B (CHB) is a major global
healthcare problem. Functional impairment of immune responses is a
key feature of chronic HBV infection. An immune enhancer is needed
to restore HBV-specific B- and T cell responses. An orally available
small molecule RO7020531 is currently being tested in Phase I with
the potential to modulate immune responses against HBV infection.
Here we report the key features of this compound and its anti-HBV
effect in preclinical studies.
Method: In vitro assessments of the potency, specificity, and
cytotoxicity were performed using appropriate cell lines overexpressing
TLR3, 7, 8, and 9 and human PBMC. In vivo efficacywas studied in
a mouse model with a recombinant adeno associated virus carrying
hepatitis B virus genome (AAV HBV) in either C57BL/6 mice or SCID
mice. The levels of HBV DNA, HBsAg, and HBeAg in mouse serum
were measured by quantitative polymerase chain reaction (qPCR),
HBsAg chemiluminescent immunoassay (CLIA), HBeAg CLIA kits, and
mouse IgG ELISA development kit, respectively.
Results: RO7020531 is a double prodrug of RO7011785, a TLR7-
selective agonist. Ex vivo stimulation of human PBMCs by RO7011785
led to the induction of IFNα and various cytokines and chemokines,
such as TNFα, IL-6 and IP-10. Depletion of plasmacytoid dendritic
cells (pDC) and monocytes in PBMC greatly reduced the production
of IFNα and IL-6, respectively, induced by RO7011785. In a mouse
model, RO7020531 stimulated type I interferon response mainly in
the spleen and lymph nodes, but not in the gastrointestinal (GI) tract.
Moreover, anti-HBV effects of RO7020531 were observed in a dosedependent
manner in the AAV-HBV mouse model, where the TLR7
agonist significantly reduced the levels of HBV DNA and HBsAg. The
innate immune response triggered by RO7020531, such as the
upregulation of cytokines and interferon-stimulated genes (ISG),
were recapitulated in the AAV-HBV model. Notably, the ability of
RO7020531 to suppress viremia and to reduce HBsAg was dependent
upon adaptive immune responses, since these antiviral effects were
largely abrogated in the AAV-HBV model using SCID mice where Tand
B cellswere absent. Indeed,we confirmed that RO7020531 promoted
the emergence of anti-HBs antibody in the serum and increased
HBsAg-specific T and B cells in the spleen.
Conclusion: The small molecule RO7020531 represents a promising
anti-HBV agent with the potential to trigger innate and HBV-specific
adaptive immune responses to reduce HBV DNA and HBsAg. These
unique featureswarrant further evaluation of the anti-HBV efficacy of
this molecule in a clinical setting.
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发表于 2018-4-18 19:36