Cargando…
Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance
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. DES...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359590/ https://www.ncbi.nlm.nih.gov/pubmed/36316098 http://dx.doi.org/10.1136/gutjnl-2022-327059 |
_version_ | 1785075917833371648 |
---|---|
author | Meng, Chao-Yang Sun, Shiyu Liang, Yong Xu, Hairong Zhang, Chao Zhang, Min Wang, Fu-Sheng Fu, Yang-Xin Peng, Hua |
author_facet | Meng, Chao-Yang Sun, Shiyu Liang, Yong Xu, Hairong Zhang, Chao Zhang, Min Wang, Fu-Sheng Fu, Yang-Xin Peng, Hua |
author_sort | Meng, Chao-Yang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10359590 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-103595902023-07-22 Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance Meng, Chao-Yang Sun, Shiyu Liang, Yong Xu, Hairong Zhang, Chao Zhang, Min Wang, Fu-Sheng Fu, Yang-Xin Peng, Hua Gut Hepatology 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. BMJ Publishing Group 2023-08 2022-10-31 /pmc/articles/PMC10359590/ /pubmed/36316098 http://dx.doi.org/10.1136/gutjnl-2022-327059 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Hepatology Meng, Chao-Yang Sun, Shiyu Liang, Yong Xu, Hairong Zhang, Chao Zhang, Min Wang, Fu-Sheng Fu, Yang-Xin Peng, Hua Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance |
title | Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance |
title_full | Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance |
title_fullStr | Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance |
title_full_unstemmed | Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance |
title_short | Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance |
title_sort | engineered anti-pdl1 with ifnα targets both immunoinhibitory and activating signals in the liver to break hbv immune tolerance |
topic | Hepatology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359590/ https://www.ncbi.nlm.nih.gov/pubmed/36316098 http://dx.doi.org/10.1136/gutjnl-2022-327059 |
work_keys_str_mv | AT mengchaoyang engineeredantipdl1withifnatargetsbothimmunoinhibitoryandactivatingsignalsinthelivertobreakhbvimmunetolerance AT sunshiyu engineeredantipdl1withifnatargetsbothimmunoinhibitoryandactivatingsignalsinthelivertobreakhbvimmunetolerance AT liangyong engineeredantipdl1withifnatargetsbothimmunoinhibitoryandactivatingsignalsinthelivertobreakhbvimmunetolerance AT xuhairong engineeredantipdl1withifnatargetsbothimmunoinhibitoryandactivatingsignalsinthelivertobreakhbvimmunetolerance AT zhangchao engineeredantipdl1withifnatargetsbothimmunoinhibitoryandactivatingsignalsinthelivertobreakhbvimmunetolerance AT zhangmin engineeredantipdl1withifnatargetsbothimmunoinhibitoryandactivatingsignalsinthelivertobreakhbvimmunetolerance AT wangfusheng engineeredantipdl1withifnatargetsbothimmunoinhibitoryandactivatingsignalsinthelivertobreakhbvimmunetolerance AT fuyangxin engineeredantipdl1withifnatargetsbothimmunoinhibitoryandactivatingsignalsinthelivertobreakhbvimmunetolerance AT penghua engineeredantipdl1withifnatargetsbothimmunoinhibitoryandactivatingsignalsinthelivertobreakhbvimmunetolerance |