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A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic
Binfan Chen1, Yuchen Chen2, Jian Li3
1MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Engineering Research Center for Synthetic Immunology, School of Basic Medical Sciences, Fudan Universitygrid.8547.e, Shanghai, China.
Insights
New mRNA drugs encoding antibodies show promise for a functional cure of chronic hepatitis B (CHB) infection. These advanced therapies achieved sustained suppression of hepatitis B surface antigen (HBsAg) in mice, offering a potential new treatment strategy.
Area of Science:
- Hepatitis B Virus (HBV) Research
- Immunotherapy
- mRNA Therapeutics
Background:
- Hepatitis B virus (HBV) infection affects over 250 million people globally, causing severe liver diseases.
- Current treatments struggle to achieve persistent suppression of hepatitis B surface antigen (HBsAg), a key goal for a functional cure of chronic hepatitis B (CHB).
- Antibody-based treatments targeting HBsAg show potential for restoring immune responses and aiding HBV cure.
Purpose of the Study:
- To develop and evaluate advanced mRNA drugs encoding anti-HBsAg antibodies for sustained HBsAg suppression.
- To investigate the efficacy of mRNA-lipid nanoparticles (LNPs) delivering anti-HBsAg antibody genes in a mouse model.
Main Methods:
- Engineered mRNA-lipid nanoparticles (LNPs) to encode three anti-HBsAg antibodies: G12-scFv, G12-scFv-Fc, and G12-IgG.
- Administered a single dose of mL (G12-scFv-Fc) and mL (G12-IgG) to an adeno-associated virus (AAV)/HBV mouse model.
- Monitored serum HBsAg and HBV DNA levels post-administration.
Main Results:
- Single-dose mRNA-LNPs (mL (G12-scFv-Fc) and mL (G12-IgG)) significantly reduced serum HBsAg levels within 30 days in mice.
- Exogenous antibodies showed a transient effect, losing efficacy in reducing HBsAg or HBV DNA after 9 days.
- The combination of high-affinity antibodies and mRNA-LNP adjuvant activity led to long-term HBsAg seroclearance.
Conclusions:
- mRNA-LNPs encoding anti-HBsAg antibodies offer a promising strategy for sustained HBsAg suppression in chronic hepatitis B.
- This approach demonstrates potential for a functional cure of HBV by facilitating immune system re-establishment.
- mRNA therapeutics represent a versatile platform for infectious disease treatment, including HBV, due to rapid development and simplicity.
Abstract:
Hepatitis B virus (HBV) infection is a serious global health issue with more than 250 million chronic carriers. It causes liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Persistent suppression of the HBV surface antigen (HBsAg) is necessary for a functional cure of chronic hepatitis B (CHB) virus infection. However, this can hardly be achieved with currently approved drugs. Antibody treatment against HBsAg has shown promise in restoring HBV-specific immune responses and promoting HBV cure. To achieve long-lasting HBsAg suppression, we used an advanced mRNA drug to encode the genes of three anti-HBsAg antibodies, G12-scFv, G12-scFv-Fc, and G12-IgG. Antibody-encoding mRNA-lipid nanoparticles (LNPs), mL (G12-scFv-Fc) and mL (G12-IgG), substantially reduced serum HBsAg levels in treated mice within 30 days after a single dose. In contrast, exogenous antibodies lost effect on reducing HBsAg or HBV DNA levels 9 days postadministration. The high affinity of anti-HBsAg antibodies and the adjuvant activity of mRNA-LNPs resulted in long-term HBsAg seroclearance, which could contribute to the reestablishment of the immune system in HBV carriers. These findings highlight the great potential of antibody-encoding mRNA molecules against CHB infection. IMPORTANCE It is the first time that mRNA-LNPs have been used to express anti-HBsAg antibodies (G12-scFv, G12-scFv-Fc, and G12-IgG). G12-scFv-Fc- and G12-IgG-encoding mRNA-LNPs exerted a sustained effect on HBsAg serum clearance in the adeno-associated virus (AAV)/HBV mouse model with persistent HBsAg expression. These findings may provide a new design of combination therapy for functional cure of HBV. For example, this strategy could provide an alternative for antibodies in "sandwich" therapy and further enhance the immunization properties of the therapy. Overall, mRNA therapeutics are promising for treatment of infectious diseases because of their rapid development, economic value, and simplicity.
