家蠶生物反應(yīng)器產(chǎn)業(yè)化體系與產(chǎn)品開發(fā)

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(chǎn)業(yè)化生產(chǎn)的生物反應(yīng)器，做為其中之一的昆蟲桿狀病毒系統(tǒng)，生產(chǎn)成本相對較低，能表達(dá)許多具有生物活性的哺乳動(dòng)物的基因，與其他表達(dá)系統(tǒng)相比，具有明顯的優(yōu)勢。家蠶是目前唯一能進(jìn)行此項(xiàng)工作且能大規(guī)模人工飼養(yǎng)的經(jīng)濟(jì)昆蟲。通過體外基因重組獲得重組桿狀病毒，在昆蟲細(xì)胞或蟲體中進(jìn)行表達(dá)，該方法操作簡便、表達(dá)量高、穩(wěn)定性好。并且家蠶生物反應(yīng)器具有中國特色，是目前最有前景的高效生產(chǎn)生物制品的昆蟲桿狀病毒表達(dá)系統(tǒng)。我們首次提出用基因工程表達(dá)hGM-CSF的家蠶蛹研制口服藥物，經(jīng)小鼠動(dòng)物實(shí)驗(yàn)表明，能使化療后的小鼠白細(xì)胞顯著上升，2004該藥物經(jīng)SFDA批準(zhǔn)已進(jìn)入臨床試驗(yàn)。這一給藥形式的改變具有重大的理論意義和生產(chǎn)應(yīng)用前景。家蠶生物反應(yīng)器蛋白質(zhì)藥物規(guī)?；苽浼夹g(shù)是目前蛋白質(zhì)藥物實(shí)現(xiàn)產(chǎn)業(yè)化的關(guān)鍵技術(shù)之一，同時(shí)其技術(shù)水平的高低也是這些藥物取得市場價(jià)格競爭優(yōu)勢的關(guān)鍵。鹿茸是鹿科動(dòng)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(yīng)器而加以利用，來生產(chǎn)那些價(jià)格昂貴的生物活性因子。生產(chǎn)的鹿茸中將含有其特有的活性成分，以及其他細(xì)胞因子等昂貴的藥用物質(zhì)。利用動(dòng)物生物反應(yīng)器生產(chǎn)藥用蛋白的市場潛力巨大。目前我們以家蠶生物反應(yīng)器和轉(zhuǎn)基因哺乳動(dòng)物器官生物反應(yīng)器—鹿茸為基礎(chǔ)，利用家蠶生物反應(yīng)器大批量的進(jìn)行外源蛋白和病毒疫苗的表達(dá)，并建立了新型的外源蛋白大量純化的技術(shù)平臺體系，為實(shí)現(xiàn)其產(chǎn)業(yè)化生產(chǎn)奠定了基礎(chǔ)；目前課題的研究工作已經(jīng)取得了一定的階段性成果。建立擁有自主知識產(chǎn)權(quán)的國際首例轉(zhuǎn)基因哺乳動(dòng)物器官生物反應(yīng)器，同時(shí)選擇合適的目的基因進(jìn)行表達(dá)，將會(huì)帶來巨大的經(jīng)濟(jì)和社會(huì)價(jià)值。

關(guān)鍵詞：家蠶生物反應(yīng)器 hGM-CSF 疫苗 鹿茸生物反應(yīng)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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