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821
-ANTIGEN TRAFFIC-INHIBITING OLIGONUCLEOTIDE
POLYMERS (STOPS) EFFECTIVELY INHIBIT HEPATITIS B
SURFACE ANTIGEN (HBsAg) SECRETION IN BOTH HEPATITIS
B VIRUS (HBV) CELL LINES AND HBV INFECTED CELLS
Yuchun Nie1, Hua Tan2, Cheng Kao3, Suping Ren2, Rajendra
Pandey2, Sushmita Chanda2, Lawrence Blatt2, Leonid N.
Beigelman2, Julian A. Symons2 and Jin Hong2, (1)Biology,
Aligos Therapeutics. Llc, (2)Aligos Therapeutics, Inc., (3)
Aligos Therapeutics
Background: Current standard of care for chronic hepatitis
B (CHB) is highly effective in suppressing viral replication but
fails to reduce HBsAg that suppresses the human immune
system and prevents the attainment of “functional cure”
Nucleic acid polymers (NAPs) such as REP-2139 significantly
reduce circulating HBsAg in CHB patients when given as
monotherapy1 and in combination therapy2. We have identified
STOPS that share structural similarity with NAPs but contain
novel and enhanced chemical features3 Here, we report the
HBsAg reduction activity of ALG-010133 in multiple HBV cell
lines Methods: Compounds were profiled in HepG2.2.15,
a commonly used genotype D (Gt D) HBV cell model, PLC/
PRF 5 (model for integrated HBV, that only produces HBsAg
with no virions) HepG2-GtA, HepG2-GtB, HepG2-NTCP and
primary human hepatocyte (PHH) live HBV infection systems
In HepG2 2 15, HepG2-GtA, HepG2-GtB and PLC/PRF 5,
compounds were administered by reverse transfection using
Lipofectamine® RNAiMAX HepG2-NTCP cells and PHH
cells were infected with HBV of different genotypes at 200 moi
(ge) and transfected with STOPS five days later. The secreted
HBsAg and HBeAg were quantitated by ELISA on day 6 posttreatment
Results: ALG-010133 inhibited HBsAg release
with EC50 values of 3 9 and 23 7 nM in HepG2 2 15 and PLC/
PRF 5 respectively and EC50 values of 3 2 and 5 9 nM from
HBV infected HepG2-NTCP and PHH cells respectively ALG-
010133 demonstrated cross genotypic activity: inhibiting the
HBsAg release in cells containing Gt A, B, C and D viruses
with EC50 values of 7 9, 9 25, 0 72 and 3 9 nM respectively
Additionally, intracellular HBsAg was also reduced,
suggesting that HBsAg was degraded rather than trapped
intracellularly HBeAg secretion was inhibited concomitantly
with HBsAg. In a human PBMC assay, no specific cytokines
were induced by ALG-010133 suggesting a low potential for
the induction of injection site reactions Conclusion: ALG-
010133 demonstrated robust, pan-genotypic inhibition of
HBsAg release in multiple cell lines and infected liver cells,
with enhanced activity compared to REP-2139 ALG-010133
inhibited HBsAg from the partial HBV genome integrated
PLC/PRF 5 cell line, indicating the potential for reducing
HBsAg in CHB patients with a high degree of HBV integration |
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发表于 2020-10-17 20:34
