Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance.
Gut
; 72(8): 1544-1554, 2023 Aug.
Article
en En
| MEDLINE
| ID: mdl-36316098
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Virus de la Hepatitis B
/
Hepatitis B Crónica
Límite:
Animals
Idioma:
En
Revista:
Gut
Año:
2023
Tipo del documento:
Article
País de afiliación:
China