Hepatitis B is the most common serious liver disease caused by hepatitis B virus (HBV) infection. Most adults infected with HBV have little or no symptoms and can rely on the immune system to clear HBV. This process is known as HBV acute infection and may take up to 6 months. On the contrary, most infants or young children infected with HBV can not resist virus replication and are more likely to develop a long-lasting chronic hepatitis B (CHB) infection.
At present, there are 257 million chronic HBV infections in the world. A high level of HBV replication can significantly change the antibody repertoires in patients with chronic hepatitis B and induce T-cell and B-cell function deficiency, causing persistent HBV infection, which might develop into liver cirrhosis and eventually lead to liver failure and liver cancer. The impaired host immune system and persistent cccDNA are the main obstacles to HBV clearance, making it impossible to cure hepatitis B. The remarkable feature of the functional cure of CHB is that HBsAg can not be detected in serum, which is also the main goal of the current treatment for chronic hepatitis B. Currently, valid drugs for the treatment of chronic hepatitis B, such as nucleoside analogues and pegylated interferon, can only achieve less than 10% functional cure from chronic hepatitis B virus infections.
Some researchers have proposed to achieve a functional cure for chronic hepatitis B infection through antibody therapy. However, anti-HBsAg can only neutralize hepatitis B surface antigen within a very limited duration. Meanwhile, antibody production is a very complex, time-consuming, and expensive project, which greatly limits the widespread application of antibody therapy in the field of infectious diseases. mRNA technology, due to its immune advantages and simplified synthetic production process, shows unique advantages in the research and production of viral vaccines. However, at present, there are only a few cases that apply mRNA technology to passive immunization to produce monoclonal antibodies.
In 2021, mRNA technology was used to encode neutralizing antibodies targeting the Chikungunya virus. And its Phase 1 clinical data confirmed the effectiveness of this method. This is the first clinical trial that mRNA technology is used to develop monoclonal neutralizing antibodies.
Recently, Ying Tianlei Research Group of Fudan University and Lin Jinzhong Research Group jointly published a research paper entitled “A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: A Potential Cure of Chronic Hepatitis B Virus Infection” in the mBio journal.
In this study, the mRNA technique was used for the first time to encode anti-HBsAg antibodies. The clearance ability of serum hepatitis B surface antigen induced by injection of one dose of G12-mRNA-LNP into the chronic hepatitis B mouse model lasted for at least 30 days, thus significantly reducing the level of serum hepatitis B surface antigen.
In contrast, exogenous monoclonal antibodies lost their inhibitory effect on the clearance of serum hepatitis B surface antigen 9 days postadministration. The preliminary data obtained from this work shows that the treatment of chronic hepatitis B by mRNA-LNP encoding hepatitis B surface antigen is a very promising new therapy.
Clearance of serum HBsAg has always been regarded as a long-term goal of anti-HBV therapy. Anti-HBsAg can directly inhibit HBsAg in serum in the functional treatment of chronic hepatitis B. This work uses mRNA technology to express anti-HBsAg IgG for the first time, and in the mouse model, it is proved that injection of anti-HBsAg IgG-encoding mRNA-LNPs has more lasting and significant serum HBsAg clearance ability than direct injection of the corresponding antibody. This suggests that the adjuvant effect triggered by mRNA molecules and liposome components may enhance the clearance of serum HBsAg.
LNP mainly delivers mRNA to liver cells, which makes mRNA-LNP technology an ideal platform for the treatment of liver diseases. Compared with the tedious, time-consuming, and expensive production process of monoclonal antibodies, the production process of mRNA is more rapid, convenient, and universal. In the ‘Sandwich’ therapy of chronic hepatitis B, replacing the corresponding monoclonal antibody with mRNA-LNPs encoding hepatitis B surface antigen antibodies will become a very promising new therapy in the future.