Yiping Li1, Zhengwen Liu2,3, Lingyun Hui4, Xi Liu5, Ai Feng4, Wei Wang4, Lin Zhang4, Na Li2, Guoqing Zhou6, Quanli Wang7, Qunying Han2, Yi Lv3,8, Quanying Wang9, Guangxiao Yang9, Yawen Wang4. 1. School of Pharmacy, Xi'an Jiaotong University, Xi'an, China. 2. Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China. 3. Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, China. 4. Department of Laboratory Medicine, First Affiliated Hospital, School of medicine, Xi'an Jiaotong University, Xi'an, China. 5. Department of Pathology, First Affiliated Hospital, School of medicine, Xi'an Jiaotong University, Xi'an, China. 6. School of Computer Science and Engineering, Northwestern Polytechnical University, Xi'an, China. 7. Department of Epidemiology and Statistics, School of medicine, Xi'an Jiaotong University, Xi'an, China. 8. Department of Hepatobiliary Surgery, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China. 9. Xi'an Hua Guang Biological Engineering Company, Xi'an, China.
Abstract
BACKGROUND AND PURPOSE: The therapeutic management of hepatitis B virus (HBV) infections remains challenging, and novel antiviral strategies are urgently required. The HBV transbody, a monoclonal antibody (MAb) against human HBcAg coupled with the trans-activator of transcription protein transduction domain (TAT PTD), was previously shown to possess cell-penetrating ability and potent antiviral activity in vitro. The purpose of the present study was to evaluate the antiviral activity of the HBcMAb-TAT PTD conjugate in vivo in a duck model of HBV. EXPERIMENTAL APPROACH: Female Peking ducks were injected i.p. with 0.03-0.3 mg·kg-1 ·day-1 of the DHBV transbody (DHBcMAb-TAT PTD conjugate) for 30 days. Serum DHBV DNA levels and liver DHBV DNA and covalently closed circular DNA (cccDNA) loads were determined at scheduled time points. Immunohistological examination of DHBcAg in the duck liver was also performed. KEY RESULTS: The DHBV transbody significantly reduced the serum and liver DHBV DNA levels at doses of 0.1 and 0.3 mg·kg-1 ·day-1 and liver cccDNA levels at a dose of 0.3 mg·kg-1 ·day-1 after 30 days of treatment. The suppressive effects of the DHBV transbody at 0.3 mg·kg-1 ·day-1 on the serum and liver DHBV DNA and liver cccDNA levels remained significant, even at 15 days after treatment cessation. Similarly, immunohistochemistry of liver sections revealed decreased DHBcAg levels within hepatocytes 15 days after treatment termination. CONCLUSIONS AND IMPLICATIONS: The DHBV transbody inhibits DHBV replication and possesses potent anti-DHBV activities in vivo. The cell-permeable antibody against the virus core antigen may be developed as a novel treatment for patients with hepadnavirus infections.
BACKGROUND AND PURPOSE: The therapeutic management of hepatitis B virus (HBV) infections remains challenging, and novel antiviral strategies are urgently required. The HBV transbody, a monoclonal antibody (MAb) against human HBcAg coupled with the trans-activator of transcription protein transduction domain (TAT PTD), was previously shown to possess cell-penetrating ability and potent antiviral activity in vitro. The purpose of the present study was to evaluate the antiviral activity of the HBcMAb-TAT PTD conjugate in vivo in a duck model of HBV. EXPERIMENTAL APPROACH: Female Peking ducks were injected i.p. with 0.03-0.3 mg·kg-1 ·day-1 of the DHBV transbody (DHBcMAb-TAT PTD conjugate) for 30 days. Serum DHBV DNA levels and liver DHBV DNA and covalently closed circular DNA (cccDNA) loads were determined at scheduled time points. Immunohistological examination of DHBcAg in the duck liver was also performed. KEY RESULTS: The DHBV transbody significantly reduced the serum and liver DHBV DNA levels at doses of 0.1 and 0.3 mg·kg-1 ·day-1 and liver cccDNA levels at a dose of 0.3 mg·kg-1 ·day-1 after 30 days of treatment. The suppressive effects of the DHBV transbody at 0.3 mg·kg-1 ·day-1 on the serum and liver DHBV DNA and liver cccDNA levels remained significant, even at 15 days after treatment cessation. Similarly, immunohistochemistry of liver sections revealed decreased DHBcAg levels within hepatocytes 15 days after treatment termination. CONCLUSIONS AND IMPLICATIONS: The DHBV transbody inhibits DHBV replication and possesses potent anti-DHBV activities in vivo. The cell-permeable antibody against the virus core antigen may be developed as a novel treatment for patients with hepadnavirus infections.
Authors: Michael J Curtis; Richard A Bond; Domenico Spina; Amrita Ahluwalia; Stephen P A Alexander; Mark A Giembycz; Annette Gilchrist; Daniel Hoyer; Paul A Insel; Angelo A Izzo; Andrew J Lawrence; David J MacEwan; Lawrence D F Moon; Sue Wonnacott; Arthur H Weston; John C McGrath Journal: Br J Pharmacol Date: 2015-07 Impact factor: 8.739