The Peng Hua group has made new progress in the treatment of chronic hepatitis B

Hepatitis B virus (HBV) infection is a major public health problem worldwide, with approximately 257 million people living
with chronic HBV worldwide.
Globally, approximately 887 000 people die each year from HBV infection-related diseases, which is responsible for 30% of people with cirrhosis and 45
% of patients with primary hepatocellular carcinoma (HCC).
Among patients with cirrhosis and HCC in China, HBV is caused by 77% and 84%,
respectively.
At present, the prevalence of HBsAg in the general population of China is 5%~6%, and there are about 70 million cases of chronic HBV infection, of which about 20 million ~ 30 million cases
of chronic hepatitis B (CHB) patients.

Prophylactic hepatitis B vaccine has a good protective effect, and vaccination with prophylactic hepatitis B vaccine greatly reduces the rate of HBV infection, but does not produce neutralizing antibodies to clear the virus
in CHB patients.
At present, the drugs approved for the treatment of CHB include type I interferons (IFNs) and 5 nucleoside (acid) analogues (NAs), which can inhibit the replication of HBV, but it is difficult to achieve the functional cure
of CHB with "surface antigen (HBsAg) negative conversion with or without the appearance of surface antibodies (anti-HBs), undetectable HBV DNA, etc.
".
With low response rate and side effects of systemic IFN administration (subcutaneous or intramuscular), how to overcome the shortcomings of systemic IFN administration and achieve functional cure of CHB is a very challenging problem
.

On October 31, 2022, Professor Peng Hua of the Institute of Biophysics of the Chinese Academy of Sciences and Professor Yangxin Fu of the School of Medicine of Tsinghua University published an online publication entitled "Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to" in the journal Gut break HBV immune tolerance"
.
Researchers have developed an anti-PDL1 antibody fusion protein with IFNα (anti-PDL1-IFNα), which uses anti-PDL1 to target IFNα to the liver to achieve local IFNα antiviral and immune modulatory effects, improve the effectiveness of IFNα and reduce side effects
.

Anti-PDL1-IFNα fusion protein breaks HBV-induced immune tolerance through three aspects: (1) targeting IFNα to the liver to inhibit HBV replication, reduce viral load, and exert IFNα direct antiviral effects; (2) IFNα was targeted to dendritic cells (DCs) in the liver, and the co-stimulatory molecules CD80, CD86 and MHCI of DC cells and their antigen presentation ability were upregulated to promote the function of HBV-specific T cells; (3) Give play to the role of immune checkpoint blockade, overcome PDL1-mediated immunosuppression, and achieve immunomodulatory effect
.
The therapeutic effect of anti-PDL1-IFNα fusion protein was significantly higher than that of IFNα or anti-PDL1 monotherapy and the combination of IFNα and anti-PDL1
.
The researchers found that IFNα-induced upregulation of PDL1 in the liver in the fusion protein is conducive to the more effective liver targeting of anti-PDL1-IFNα, and realizes the synergistic antiviral effect
of anti-PDL1 and IFNα in the anti-PDL1-IFNα fusion protein 。 Studies have proved that the immunomodulatory effect of anti-PDL1-IFNα fusion protein and its antiviral effect are used to reduce the levels of HBsAg and HBV-DNA in the liver and peripheral blood, providing a "window period" for breaking immune tolerance.
The combination vaccine active immunity can induce host HBV-specific T cell and B cell responses to achieve a functional cure
of chronic hepatitis B.

Anti-PDL1-IFNα fusion protein combined with hepatitis B vaccine promotes the functional cure of CHB

Meng Chaoyang, assistant researcher at the Institute of Biophysics, Chinese Academy of Sciences, is the first author of this paper; Professor Peng Hua from the Institute of Biophysics, Chinese Academy of Sciences and Professor Yangxin Fu from the School of Medicine of Tsinghua University are the co-corresponding authors of this paper, and are strongly supported
by the team of Academician Wang Fusheng of the Fifth Medical Center of the Chinese People's Liberation Army General Hospital.
The research was funded
by the National Science and Technology Major Project.
The laboratory animal platform and public technology platform of the Institute of Biophysics provided important support and assistance
for this research.

Link to the article: https://gut.
bmj.
com/content/early/2022/10/31/gutjnl-2022-327059

(Contributed by: Peng Hua Research Group)