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EASL 2019 FRI-184
Function and drug combination studies in cell culture models for
AB-729, a subcutaneously administered siRNA investigational
agent for chronic hepatitis B infection
Amy C.H. Lee1, Emily P. Thi1, Andrea Cuconati1, Andrzej Ardzinski1,
Richard Holland1, Hui Huang1, Andrew S. Kondratowicz1,
Rose Kowalski1, Lorne Palmer1, Chris Pasetka1, Rene Rijnbrand1,
Holly M. Steuer1, Xiaohe Wang1, Xin Ye1, Michael J. Sofia1. 1Arbutus
Biopharma, Warminster, United States
Email: [email protected]
Background and aims: Developing a cure for chronic hepatitis B
must address viral persistence and likely requires combination of
drugs with different modes of action. AB-729 is a siRNA agent that
acts on all HBV RNA transcripts, enabling inhibition of HBV
replication and suppression of all viral antigens including HBsAg;
this may facilitate reinvigoration of host immune responses. A novel
high avidity N-acetylgalactosamine (GalNAc) moiety mediates
targeting of AB-729 to hepatocytes, the site of HBV infection. Here
we describe HBV cell culture models capable of demonstrating both
cellular entryand gene silencing functionalities of GalNAc-siRNA, and
present in vitro characterization of AB-729 anti-HBV activities as
monotherapy as well as in combination with approved and
investigational drug modalities.
Method: AB-729 activity was studied in adeno-associated virustransduced
HBV-expressing primary mouse hepatocytes (PMH),
HBV-infected primary human hepatocytes (PHH) and transientlyand
stably-transfected HBV cell lines. Drug combination studieswere
conducted using three-dimensional modeling for drug-drug interactions
and analyzed using MacSynergy II software.
Results: Asialoglycoprotein receptor (ASGPR) levels decreased
rapidly during in vitro culture of primary hepatocytes, providing a
narrow time window for GalNAc-mediated cellular entry of AB-729.
Congruent with this, EC50 shifts of 24- and at least 478-fold were
observed in PMH and PHH treated with GalNAc-siRNA at 4 h
compared to 24 h or 4 days post-plating. AB-729 reduced HBV RNA,
HBeAg and HBsAg expression, with 5.6-19.4 nM EC50 values in PMH.
Commercial transfection agent had to be utilized to conduct a
standard HBV genotype and resistance mutant susceptibility panel
for the siRNA component of AB-729. Pairwise testing with tenofovir
alafenamide, peg-interferon-alpha-2a and AB-506, a next-generation
investigational capsid inhibitor, showed that AB-729 was able to
combine productively with each of these drug modalities and
without significant effects on cell viability.
Conclusion: Standard HBV cell lines can be used to characterize the
activity of the AB-729 siRNA whereas two primary hepatocyte
systems were able to model both the cell entry functionality and
anti-HBV activities of AB-729. Preclinical investigations demonstrate
that AB-729 and AB-506 when combined have distinct but
mechanistically compatible antiviral activities and may feasibly be
used in future combination therapeutic regimens. |
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发表于 2019-4-20 15:16
