A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic Hepatitis B Virus Infection
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...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01612-22 |
| _version_ | 1811281738112958464 |
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| author | Binfan Chen Yuchen Chen Jian Li Chunyu Wang Wenping Song Yumei Wen Jinzhong Lin Yanling Wu Tianlei Ying |
| author_facet | Binfan Chen Yuchen Chen Jian Li Chunyu Wang Wenping Song Yumei Wen Jinzhong Lin Yanling Wu Tianlei Ying |
| author_sort | Binfan Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T01:38:59Z |
| format | Article |
| id | doaj.art-ad18c172f8f04e5794d50c65a08fb356 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-13T01:38:59Z |
| publishDate | 2022-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-ad18c172f8f04e5794d50c65a08fb3562022-12-22T03:08:15ZengAmerican Society for MicrobiologymBio2150-75112022-08-0113410.1128/mbio.01612-22A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic Hepatitis B Virus InfectionBinfan Chen0Yuchen Chen1Jian Li2Chunyu Wang3Wenping Song4Yumei Wen5Jinzhong Lin6Yanling Wu7Tianlei Ying8MOE/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 University, Shanghai, ChinaState Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, ChinaClinical Laboratory Center, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, ChinaMOE/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 University, Shanghai, ChinaMOE/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 University, Shanghai, ChinaMOE/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 University, Shanghai, ChinaState Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, ChinaMOE/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 University, Shanghai, ChinaMOE/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 University, Shanghai, ChinaABSTRACT 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.https://journals.asm.org/doi/10.1128/mbio.01612-22HBV infectionHBsAgfunctional cureimmune responseantibodymRNA |
| spellingShingle | Binfan Chen Yuchen Chen Jian Li Chunyu Wang Wenping Song Yumei Wen Jinzhong Lin Yanling Wu Tianlei Ying A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic Hepatitis B Virus Infection mBio HBV infection HBsAg functional cure immune response antibody mRNA |
| title | A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic Hepatitis B Virus Infection |
| title_full | A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic Hepatitis B Virus Infection |
| title_fullStr | A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic Hepatitis B Virus Infection |
| title_full_unstemmed | A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic Hepatitis B Virus Infection |
| title_short | A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic Hepatitis B Virus Infection |
| title_sort | single dose of anti hbsag antibody encoding mrna lnps suppressed hbsag expression a potential cure of chronic hepatitis b virus infection |
| topic | HBV infection HBsAg functional cure immune response antibody mRNA |
| url | https://journals.asm.org/doi/10.1128/mbio.01612-22 |
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