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. Design We designed an anti-PDL1-IFN alpha heterodimeric fusion protein, in which one arm was derived from anti-PDL1 antibody and the other arm was IFN alpha, to allow targeted delivery of IFN alpha into the liver by anti-PDL1 antibody. The effect of the anti-PDL1-IFN alpha heterodimer on overcoming hepatitis B surface antigen (HBsAg) vaccine resistance was evaluated in chronic HBV carrier mice. Results The anti-PDL1-IFN alpha 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-IFN alpha 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-IFN alpha heterodimer can break HBV-induced immune tolerance to an HBsAg vaccine, offering a promising translatable therapeutic strategy for the functional cure of CHB.

Automated summary

The study aims to develop an anti-PDL1-IFN alpha fusion protein to overcome immune tolerance induced by chronic hepatitis B virus (HBV) and combine it with a HBV vaccine to achieve functional cure for chronic hepatitis B infection.