单剂量抗 HBsAg 抗体编码 mRNA-LNP 抑制 HBsAg 表达：慢性乙型肝

StephenW

单剂量抗 HBsAg 抗体编码 mRNA-LNP 抑制 HBsAg 表达：慢性乙型肝炎病毒感染的潜在治愈方法
陈彬凡#1、陈雨辰#2、李健#3、王春雨1、宋文萍1、文玉梅1、林晋中2、吴彦玲1、应天雷1
隶属关系
隶属关系

    1
    MOE/NHC/CAMS医学分子病毒学重点实验室，上海传染病与生物安全研究所，上海合成免疫工程研究中心，基础医学院，复旦大学grid.8547.e，上海，中国。
    2
    复旦大学中山医院生命科学学院基因工程国家重点实验室grid.8547.e，上海，中国。
    3
    复旦大学儿童医院临床检验中心grid.8547.e，国家儿童医学中心，上海，中国。

#
同等贡献。

    PMID：35862767 DOI：10.1128/mbio.01612-22

抽象的

乙型肝炎病毒 (HBV) 感染是一个严重的全球健康问题，有超过 2.5 亿慢性携带者。它会导致肝脏疾病，例如慢性肝炎、肝硬化和肝细胞癌 (HCC)。持续抑制 HBV 表面抗原 (HBsAg) 对于慢性乙型肝炎 (CHB) 病毒感染的功能性治愈是必要的。然而，目前批准的药物很难做到这一点。针对 HBsAg 的抗体治疗已显示出恢复 HBV 特异性免疫反应和促进 HBV 治愈的希望。为了实现持久的 HBsAg 抑制，我们使用一种先进的 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 天内显着降低了治疗小鼠的血清 HBsAg 水平。相反，外源性抗体在给药后 9 天失去了降低 HBsAg 或 HBV DNA 水平的作用。抗 HBsAg 抗体的高亲和力和 mRNA-LNP 的佐剂活性导致长期 HBsAg 血清学清除，这可能有助于重建 HBV 携带者的免疫系统。这些发现突出了编码抗体的 mRNA 分子对抗 CHB 感染的巨大潜力。重要性 这是首次使用 mRNA-LNP 表达抗 HBsAg 抗体（G12-scFv、G12-scFv-Fc 和 G12-IgG）。编码 G12-scFv-Fc 和 G12-IgG 的 mRNA-LNP 对 HBsAg 持续表达的腺相关病毒 (AAV)/HBV 小鼠模型中的 HBsAg 血清清除具有持续影响。这些发现可能为HBV功能性治愈提供一种新的联合疗法设计。例如，这种策略可以为“三明治”疗法中的抗体提供替代方案，并进一步增强该疗法的免疫特性。总体而言，mRNA 疗法因其快速发展、经济价值和简单性而有望用于治疗传染病。

关键词：慢性乙型肝炎；乙肝病毒感染；乙肝表面抗原；抗体;功能性治愈；免疫反应; mRNA。

StephenW

A Single Dose of Anti-HBsAg Antibody-Encoding mRNA-LNPs Suppressed HBsAg Expression: a Potential Cure of Chronic Hepatitis B Virus Infection
Binfan Chen #  1 , Yuchen Chen #  2 , Jian Li #  3 , Chunyu Wang  1 , Wenping Song  1 , Yumei Wen  1 , Jinzhong Lin  2 , Yanling Wu  1 , Tianlei Ying  1
Affiliations
Affiliations

    1
    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.
    2
    State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan Universitygrid.8547.e, Shanghai, China.
    3
    Clinical Laboratory Center, Children's Hospital of Fudan Universitygrid.8547.e, National Children's Medical Center, Shanghai, China.

#
Contributed equally.

    PMID: 35862767 DOI: 10.1128/mbio.01612-22

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.

Keywords: CHB; HBV infection; HBsAg; antibody; functional cure; immune response; mRNA.

tim889

不知道这玩意儿进到哪种细胞里面了  看样子不是specific的

windu

应该是闻玉梅，三明治疗法提了很多年了吧

tim889

windu 发表于 2022-7-21 22:48
应该是闻玉梅，三明治疗法提了很多年了吧

哈哈哈 被你发现了

StephenW

回复 windu 的帖子

是的，闻玉梅是作者之一.
三明治疗法闻玉梅于2018年首次提出.遗憾的是，尚未进行基于此概念的临床试验.