MOE/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.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan Universitygrid.8547.e, Shanghai, China.
mBio. 2022 Aug 30;13(4):e0161222. doi: 10.1128/mbio.01612-22. Epub 2022 Jul 7.
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. 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.
乙型肝炎病毒 (HBV) 感染是一个严重的全球健康问题，全球有超过 2.5 亿名慢性携带者。它会导致慢性肝炎、肝硬化和肝细胞癌 (HCC) 等肝脏疾病。持续抑制乙型肝炎表面抗原 (HBsAg) 是慢性乙型肝炎 (CHB) 病毒感染功能性治愈所必需的。然而，目前批准的药物很难实现这一目标。针对 HBsAg 的抗体治疗已显示出恢复乙型肝炎病毒特异性免疫反应和促进乙型肝炎治愈的潜力。为了实现持久的 HBsAg 抑制，我们使用先进的 mRNA 药物来编码三种抗 HBsAg 抗体 G12-scFv、G12-scFv-Fc 和 G12-IgG 的基因。编码抗体的 mRNA-脂质纳米颗粒（LNP）mL(G12-scFv-Fc) 和 mL(G12-IgG) 在单次给药后 30 天内显著降低了治疗小鼠的血清 HBsAg 水平。相比之下，外源性抗体在给药后 9 天丧失了降低 HBsAg 或 HBV DNA 水平的作用。抗 HBsAg 抗体的高亲和力和 mRNA-LNP 的佐剂活性导致了长期的 HBsAg 血清清除，这可能有助于重建乙型肝炎病毒携带者的免疫系统。这些发现突出了针对 CHB 感染的编码抗体 mRNA 分子的巨大潜力。这是首次使用 mRNA-LNP 表达抗 HBsAg 抗体（G12-scFv、G12-scFv-Fc 和 G12-IgG）。G12-scFv-Fc 和 G12-IgG 编码的 mRNA-LNP 在持续表达 HBsAg 的腺相关病毒 (AAV)/HBV 小鼠模型中对 HBsAg 血清清除具有持续作用。这些发现可能为乙型肝炎的功能性治愈提供了一种新的联合治疗设计。例如，这种策略可以为“三明治”疗法中的抗体提供替代方案，并进一步增强治疗的免疫原性。总体而言，mRNA 疗法因其快速发展、经济价值和简单性而具有治疗传染病的巨大潜力。
