家蠶生物反應器產業化體系與產品開發

于威 李春義 張志芳 禇文輝

摘 要：目前已有多種研究成功并能夠產業化生產的生物反應器，做為其中之一的昆蟲桿狀病毒系統，生產成本相對較低，能表達許多具有生物活性的哺乳動物的基因，與其他表達系統相比，具有明顯的優勢。家蠶是目前唯一能進行此項工作且能大規模人工飼養的經濟昆蟲。通過體外基因重組獲得重組桿狀病毒，在昆蟲細胞或蟲體中進行表達，該方法操作簡便、表達量高、穩定性好。并且家蠶生物反應器具有中國特色，是目前最有前景的高效生產生物制品的昆蟲桿狀病毒表達系統。我們首次提出用基因工程表達hGM-CSF的家蠶蛹研制口服藥物，經小鼠動物實驗表明，能使化療后的小鼠白細胞顯著上升，2004該藥物經SFDA批準已進入臨床試驗。這一給藥形式的改變具有重大的理論意義和生產應用前景。家蠶生物反應器蛋白質藥物規?；苽浼夹g是目前蛋白質藥物實現產業化的關鍵技術之一，同時其技術水平的高低也是這些藥物取得市場價格競爭優勢的關鍵。鹿茸是鹿科動物頭部的衍生物，其生長速度驚人，可以被作為器官生物反應器而加以利用，來生產那些價格昂貴的生物活性因子。生產的鹿茸中將含有其特有的活性成分，以及其他細胞因子等昂貴的藥用物質。利用動物生物反應器生產藥用蛋白的市場潛力巨大。目前我們以家蠶生物反應器和轉基因哺乳動物器官生物反應器—鹿茸為基礎，利用家蠶生物反應器大批量的進行外源蛋白和病毒疫苗的表達，并建立了新型的外源蛋白大量純化的技術平臺體系，為實現其產業化生產奠定了基礎；目前課題的研究工作已經取得了一定的階段性成果。建立擁有自主知識產權的國際首例轉基因哺乳動物器官生物反應器，同時選擇合適的目的基因進行表達，將會帶來巨大的經濟和社會價值。

關鍵詞：家蠶生物反應器 hGM-CSF 疫苗 鹿茸生物反應器

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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