家蚕生物反应器产业化体系与产品开发

于威 李春义 张志芳 禇文辉

摘 要：目前已有多种研究成功并能够产业化生产的生物反应器，做为其中之一的昆虫杆状病毒系统，生产成本相对较低，能表达许多具有生物活性的哺乳动物的基因，与其他表达系统相比，具有明显的优势。家蚕是目前唯一能进行此项工作且能大规模人工饲养的经济昆虫。通过体外基因重组获得重组杆状病毒，在昆虫细胞或虫体中进行表达，该方法操作简便、表达量高、稳定性好。并且家蚕生物反应器具有中国特色，是目前最有前景的高效生产生物制品的昆虫杆状病毒表达系统。我们首次提出用基因工程表达hGM-CSF的家蚕蛹研制口服药物，经小鼠动物实验表明，能使化疗后的小鼠白细胞显著上升，2004该药物经SFDA批准已进入临床试验。这一给药形式的改变具有重大的理论意义和生产应用前景。家蚕生物反应器蛋白质药物规模化制备技术是目前蛋白质药物实现产业化的关键技术之一，同时其技术水平的高低也是这些药物取得市场价格竞争优势的关键。鹿茸是鹿科动物头部的衍生物，其生长速度惊人，可以被作为器官生物反应器而加以利用，来生产那些价格昂贵的生物活性因子。生产的鹿茸中将含有其特有的活性成分，以及其他细胞因子等昂贵的药用物质。利用动物生物反应器生产药用蛋白的市场潜力巨大。目前我们以家蚕生物反应器和转基因哺乳动物器官生物反应器—鹿茸为基础，利用家蚕生物反应器大批量的进行外源蛋白和病毒疫苗的表达，并建立了新型的外源蛋白大量纯化的技术平台体系，为实现其产业化生产奠定了基础；目前课题的研究工作已经取得了一定的阶段性成果。建立拥有自主知识产权的国际首例转基因哺乳动物器官生物反应器，同时选择合适的目的基因进行表达，将会带来巨大的经济和社会价值。

关键词：家蚕生物反应器 hGM-CSF 疫苗 鹿茸生物反应器

Silkworm Bioreactor Industrialization System and Product Development

Yu Wei1 Li Chunyi2 Zhang Zhifang3 Chu Wenhui2

（1.Zhejiang Sci-Tech University；2.Institute of Special Animal and Plant Sciences of CAAS；3.Biotechnology Research Institute， Chinese Academy of Agricultural Sciences）

Abstract：At present there are several successful bioreactors which can realize industrial mass production. As one of the bioreactor system， insect baculovirus expression system can express many biologically active mammalian genes. It has obvious advantages due to the relatively low cost in production when compared to other expression systems. Silkworm is the only economic insect which can carry out this work and realize mass rearing. The recombinant baculovirus can be constructed by gene recombination in vitro and then the foreign gene was expressed in insect cells or larvae. This method has the advantages of simple operation， high expression quantity and good stability. Moreover， silkworm bioreactor， with Chinese characteristics， is currently the most promising insect baculovirus expression system to efficient produce biological products. We first put forward the idea to produce oral drug using silkworm pupa to express hGM-CSF gene. The animal oral experiments showed that the the white cell level of mice increased significantly after chemotherapy. This drug was approved for clinical trials by the SFDA in 2004. It has great theoretical significance and application prospect about this change of delivery form. The drug scale preparation technology of silkworm bioreactor is one of the key technologies to realize the industrial mass production of target protein drugs. Its technical level is also the key point of drugs in market price competition. Velvet antler is the head derivatives of Cervidae animal， the growth rate is amazing. It can be used as organ bioreactor to produce the expensive biological factors. The production of velvet antler will contain the active ingredient of its own and other expensive medicinal substances. Using this bioreactor to produce recombinant protein has great potential market. At present based on the silkworm bioreactor and transgenic mammalian organs bioreactor （antler）， we use silkworm bioreactor to produce heterologous protein and virus vaccine in large quantities， to establish a technology platform system for protein purification in large scale. These have laid the foundation for the realization of its industrialization production. At present， this project has achieved some initial results. The establishment of an international first transgenic mammalian organs bioreactor with independent intellectual property rights and the selection appropriate target genes to express will bring enormous economic and social value.

Key Words：Silkworm bioreactors； hGM-CSF； Vaccine； Antler bioreactor

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