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AS002
Targeting inhibitor of apoptosis proteins (IAPs) enhances
intrahepatic antiviral immunity to clear hepatitis B virus
infection in vivo
Xiaoyong Zhang1, Kuiyuan Huang1, Wei Zhu1, Geng Zhang1,
Jiehua Chen1, Xuan Huang1, Hongyan Liu1, Yifan Zhai2,3, Dajun Yang3,
Jinlin Hou1. 1Nanfang Hospital, Southern Medical University,
Department of Infectious Diseases, Guangzhou, China; 2HealthQuest
Pharma Inc., Guangzhou, China; 3Ascentage Pharma Group Corp.
Limited, Suzhou, China
Email: [email protected]
Background and Aims: The chronic infection caused by hepatitis B
virus (HBV) remains hard to cure by current antiviral therapies.
Previous studies had shown that the inhibitor of apoptosis proteins
(IAPs) prevented TNFα-mediated killing of infected hepatocytes and resulted in HBV persistence. APG-1387 is a novel bivalent antagonist
of IAPs targeting IAPs and is well tolerated in clinical trials of cancer
therapy. Here, we evaluated the anti-HBV function of APG-1387 and
explored the underlying mechanisms in vivo.
Method: Three immunocompetent HBV carrier mouse models were
established by infection with recombinant rAAV8-HBV1.3 in C57BL/6j
mice or hydrodynamically injected with pAAV-HBV1.2 plasmid to
C57BL/6j and C3H/HeN mice strains. 20 mg/kg of APG-1387 was
injected by i.v. or i.p. once weekly. Quantification of viral DNA,
antigens and transaminases in serum and liver samples were
examined. Cell apoptosis were determined by TUNEL or cleaved caspase-
3 immunofluorescence staining. Intrahepatic T cell
responses were analyzed by flow cytometry. Transcriptomic analysis
of liver tissues after therapy was performed by RNA-seq.
Results: Compared to vehicle injection, APG-1387 treatment for 4–20
weeks in different models led to completely clearance of HBsAg,
HBeAg and HBV DNA in serum, as well as HBcAg and HBV replicative
intermediates in infected livers, and no relapse after stop therapy.
After APG-1387 injection, cleaved-caspase-3 expression in HBcAgpositive
hepatocytes was detected, and serum transaminase levels
were transiently elevated and its peak levels were associated with the
baseline HBsAg levels. However, pan-caspase inhibitor Emricasan or
Z-VAD-FMK treatment could not block the antiviral effect of APG-
1387. Furthermore, clearance of HBV by APG-1387 was found to be
associated with upregulation of intrahepatic HBV-specific CD4+ and
CD8+ T cells frequency and function. As expected, APG-1387 was
unable to clear HBV in TNFα, CD4 or CD8 deficiency mice. Finally,
Gene Set Enrichment Analysis of RNA-seq data showed that multiple
immune-related genes were upregulated by APG-1387, similar to the
genes induced in the liver during HBV clearance in chimpanzees.
Conclusion: These findings indicated that APG-1387 was able
to clear chronic HBV infection in various mouse models with a
unique induction of apoptosis and immunoregulation mechanism.
Application of IAP antagonist might represent a novel immunotherapeutic
strategy for HBV functional cure. |
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发表于 2020-8-23 12:55
