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Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance
Chao-Yang Meng 1 , Shiyu Sun 1 , Yong Liang 2 , Hairong Xu 1 , Chao Zhang 3 , Min Zhang 4 , Fu-Sheng Wang 3 , Yang-Xin Fu 5 , Hua Peng 6
Affiliations
Affiliations
1
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
2
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
3
Senior Department of Infectious Diseases, 5th Medical Center of Chinese PLA General Hospital, Beijing, China.
4
Senior Department of Liver Disease, 5th Medical Center of Chinese PLA General Hospital, Beijing, China.
5
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China [email protected] [email protected].
6
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China [email protected] [email protected].
PMID: 36316098 DOI: 10.1136/gutjnl-2022-327059
Free article
Abstract
Objective: The purpose of this study is to develop an anti-PDL1-based interferon (IFN) fusion protein to overcome the chronic hepatitis B virus (HBV)-induced immune tolerance, and combine this immunotherapy with a HBV vaccine to achieve the functional cure of chronic hepatitis B (CHB) infection.
Design: We designed an anti-PDL1-IFNα heterodimeric fusion protein, in which one arm was derived from anti-PDL1 antibody and the other arm was IFNα, to allow targeted delivery of IFNα into the liver by anti-PDL1 antibody. The effect of the anti-PDL1-IFNα heterodimer on overcoming hepatitis B surface antigen (HBsAg) vaccine resistance was evaluated in chronic HBV carrier mice.
Results: The anti-PDL1-IFNα heterodimer preferentially targeted the liver and resulted in viral suppression, the PD1/PDL1 immune checkpoint blockade and dendritic cell activation/antigen presentation to activate HBsAg-specific T cells, thus breaking immune tolerance in chronic HBV carrier mice. When an HBsAg vaccine was administered soon after anti-PDL1-IFNα heterodimer treatment, we observed strong anti-HBsAg antibody and HBsAg-specific T cell responses for efficient HBsAg clearance in chronic HBV carrier mice that received the combination treatment but not in those that received either single treatment.
Conclusions: Targeting the liver with an engineered anti-PDL1-IFNα heterodimer can break HBV-induced immune tolerance to an HBsAg vaccine, offering a promising translatable therapeutic strategy for the functional cure of CHB.
Keywords: dendritic cells; hepatitis B; immunotherapy; interferon-alpha; liver.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. |
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发表于 2022-11-6 19:27
