Chimeric antigen receptors of HBV envelope proteins inhibit hepatitis B surface antigen secretion.

ANTIBODY TARGETED THERAPY ANTIVIRAL THERAPY HEPATITIS B MOLECULAR BIOLOGY

Journal

Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R

Informations de publication

Date de publication:
16 Nov 2023
Historique:
received: 20 06 2023
accepted: 01 11 2023
medline: 17 11 2023
pubmed: 17 11 2023
entrez: 16 11 2023
Statut: aheadofprint

Résumé

Chronic hepatitis B (CHB) caused by HBV infection greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) plays critical roles in the pathogenesis of CHB. HBsAg loss is the key indicator for cure of CHB, but is rarely achieved by current approved anti-HBV drugs. Therefore, novel anti-HBV strategies are urgently needed to achieve sustained HBsAg loss. We developed multiple chimeric antigen receptors (CARs) based on single-chain variable fragments (scFvs, namely MA18/7-scFv and G12-scFv), respectively, targeting HBV large and small envelope proteins. Their impacts on HBsAg secretion and HBV infection, and the underlying mechanisms, were extensively investigated using various cell culture models and HBV mouse models. After secretory signal peptide mediated translocation into endoplasmic reticulum (ER) and secretory pathway, MA18/7-scFv and CARs blocked HBV infection and virion secretion. G12-scFv preferentially inhibited virion secretion, while both its CAR formats and crystallisable fragment (Fc)-attached versions blocked HBsAg secretion. G12-scFv and G12-CAR arrested HBV envelope proteins mainly in ER and potently inhibited HBV budding. Furthermore, G12-scFv-Fc and G12-CAR-Fc strongly suppressed serum HBsAg up to 130-fold in HBV mouse models. The inhibitory effect lasted for at least 8 weeks when delivered by an adeno-associated virus vector. CARs possess direct antiviral activity, besides the well-known application in T-cell therapy. Fc attached G12-scFv and G12-CARs could provide a novel approach for reducing circulating HBsAg.

Identifiants

DOI: 10.1136/gutjnl-2023-330537 PMID: 37973365
pubmed: 37973365
pii: gutjnl-2023-330537
doi: 10.1136/gutjnl-2023-330537
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: None declared.

Auteurs

Yang Wang (Y)

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Qiqi Li (Q)

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Cheng Li (C)

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Cong Wang (C)

Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.

Shijie Wang (S)

Deparment of Infectious Diseases, Changzheng Hospital, Navy Medical University, Shanghai, China.

Wenjie Yuan (W)

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Demin Yu (D)

Department of Infectious Diseases, Institute of Infectious and Respiratory Diseases, Sino-French Research Center for Life Science and Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
ORCID: 0000-0001-9441-8616

Ke Zhang (K)

SCG Cell Therapy Pte Ltd, Singapore.

Bisheng Shi (B)

Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.

Xiaomei Chen (X)

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Tiantian Liu (T)

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Zhenghong Yuan (Z)

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China yongxiangwang@fudan.edu.cn zhyuan@shmu.edu.cn.
ORCID: 0000-0003-0268-4891

Shuping Tong (S)

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Michael Nassal (M)

Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany.

Yu-Mei Wen (YM)

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Yong-Xiang Wang (YX)

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontier Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China yongxiangwang@fudan.edu.cn zhyuan@shmu.edu.cn.
ORCID: 0000-0003-1405-7131

Classifications MeSH