PreS2微抗体定向表达治疗策略对HBV相关性肝癌的防治作用

Hepatitis b virus (HBV) coding PreS2 protein can induce the host immune response and production of PreS2 antibody to eliminate HBV, which provides an important defensive role. Our previous studies showed that the non-replication adenovirus expressing humanized PreS2 antibody can effectively protect the original generation of liver cells from HBV infection, inhibit HBV replication, and protect the liver cell function. Experiments have shown that in mice liver cancer induced model, the adenovirus-expressed PreS2 antibody can inhibit the liver cancer occurrence and development in HBV transgenic mice induced by DEN. In order to solve the above mentioned major problems of antibody gene therapy, such as the poor safety of the vehicle and the weak effect of full-length antibody treatments), this study will construct a regulatory replicative adenovirus to express PreS2 antibodies. With good penetration and dispersion force of mini antibodies, HBV infection or replication was inhibited and the liver cell function was protected. When in the event of cancerous conditions, the regulatory element initiates the regulatory mechanism, and promotes adenovirus replication with a high scale, which increases a large number of viral copies and a high amount of antibody expression and plays a strong inhibitory function of HBV or prevention of carcinogenesis. Through the study, there is hope to establish a perfect antibody expression of gene therapy system to prevent HBV infection and HBV related liver cancer.

乙型肝炎病毒（HBV）编码的PreS2蛋白能诱发宿主免疫应答，产生PreS2抗体，为清除HBV提供重要的防御作用。我们前期承担的研究课题以人源化全长PreS2抗体有效保护人原代肝细胞不受HBV感染，抑制HBV感染或复制，保护肝细胞功能。小鼠肝癌诱导模型实验显示， PreS2抗体具有抑制DEN诱导的HBV转基因小鼠肝癌的发生和发展。为解决上述方法存在的抗体基因治疗的最大问题（载体的安全性差和治疗全长抗体的功效低），本研究构建可调控的定向表达目的基因的增殖腺病毒表达PreS2微抗体，利用微抗体的良好穿透和弥散力，抑制HBV感染或复制，保护肝细胞功能；而一旦发生癌变则由调控元件启动条件调控机制，促使腺病毒大量增殖，提高抗体基因的拷贝数和表达量，发挥更强有力抑制HBV、预防癌变功能。通过本项研究，有希望建立一种完善的抗HBV抗肝癌的双功效抗体基因治疗策略，进行HBV感染和HBV相关肝癌的防治研究。

乙型肝炎病毒（HBV）诱发肝癌（HCC）的发生是中国肝癌高发的主要因素，其中HBx和PreS2是两个最重要的癌基因蛋白。由于PreS2抗原性强，具有很强的T、B细胞识别决定簇，能诱发宿主的免疫应答，因此可利用PreS2抗体，进一步清除HBV并阻止病毒侵入正常肝细胞。本研究构建一个条件增殖型腺病毒载体介导的、表达HBV-PreS2微抗体的治疗体系，通过严谨调控的条件增殖型病毒载体携带人源化HBV-PreS2微抗体基因，在肝细胞内瞬时表达PreS2微抗体，利用微抗体的良好穿透和弥散力，抑制HBV感染或复制，保护肝细胞功能；而一旦发生细胞癌变，细胞内腺病毒载体即刻启动病毒自身的条件调控机制，促使腺病毒在癌变的细胞中特异性高拷贝增殖，大量增殖的腺病毒不但能溶解破坏癌变细胞，还能够提高抗体基因的拷贝数和表达量，发挥更强有力的抑制HBV、溶解破坏癌细胞的功能。腺病毒在癌细胞内特异性表达的PreS2微抗体、病毒结构蛋白，连同癌细胞溶解后释放出来的多种肿瘤抗原，可作为疫苗激活机体抗肿瘤免疫应答，进一步协同增强抗肝癌效应，阻断癌变进程。研究结果发现，我们构建的治疗体系 Ad5SVP-mPreS2，能够在肝癌细胞中高效复制，其表达的mPreS2不但能够抑制HBV并有效保护肝细胞功能，防止肝损伤，而且能在HBV转基因小鼠的DEN诱导模型中防止及抑制肝癌的发生发展。本项研究建立了精确靶向调控的增殖腺病毒介导mPreS2的防治策略，具有抗病毒、抗肿瘤双功效的特点，对阻断HBV感染预防肝细胞癌变具有更好的安全性和更高的疗效。

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