植物生物反应器优化策略与最新应用<sup>*</sup>

doi:10.13523/j.cb.2207066

中国生物工程杂志

2023, Vol. 43

Issue (1): 71-86 DOI: 10.13523/j.cb.2207066

综述

植物生物反应器优化策略与最新应用^*

邹奇^1,²,潘炜松³,邱健⁴,束文圣²,吴川^1,^**(

)

1 中南大学冶金与环境学院长沙 410083
2 华南师范大学生命科学学院广州 510631
3 湖南诺合新生物科技有限公司长沙 410016
4 中南大学湘雅医院长沙 410008

Recent Advances in Optimization Strategies and Applications of Plant Bioreactors

ZOU Qi^1,²,PAN Wei-song³,QIU Jian⁴,SHU Wen-sheng²,WU Chuan^1,^**(

)

1 School of Metallurgy and Environment, Central South University, Changsha 410083, China
2 School of Life Sciences, South China Normal University, Guangzhou 510631, China
3 Hunan Novomore Biotechnology Corporation, Changsha 410016, China
4 Xiangya Hospital, Central South University, Changsha 410008, China

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摘要：

随着分子生物学和植物基因工程的迅猛发展以及分子医药和现代农业等学科的交叉融合,植物生物反应器已成为分子医药农业的核心内容。利用植物生物反应器生产抗体、疫苗和功能性食品,具有规模化、成本低、安全性高、周期短等优势。2022年2月,加拿大卫生部批准了新型冠状病毒疫苗Covifenz^®,这是世界首款植物源人体疫苗,标志着以植物生物反应器为代表的分子医药农业时代的来临。综述植物叶片和种子等代表性的植物生物反应器类型,分析瞬时表达系统和稳定表达系统的构建原理和应用,探讨通过启动子和密码子优化、糖基化过程“人源化”、基因沉默抑制和蛋白酶作用抑制等优化植物生物反应器的策略,总结国内外抗体、疫苗和功能性食品等植物源产品的开发进展,以期为我国植物生物反应器的研究及其在分子医药领域的应用提供参考。

关键词： 植物生物反应器; 分子医药农业; 外源蛋白; 瞬时和稳定表达

Abstract:

Plant bioreactors have been the central part of molecular pharming. Vaccines, antibodies and functional foods produced by plant bioreactors with the benefits of cost-effectiveness, high scalability, rapid production, enabling post-translational modification, and no harmful pathogens contamination are increasingly accepted by the public. In February 2022, Health Canada approved the world’s first plant-derived human vaccine Covifenz^® for the prevention and treatment of COVID-19, marking the advent of the era of molecular pharming represented by plant bioreactors. This paper elaborates the development history of plant bioreactors, with the main host species representatives of leafy plants and seed plants, the stable and transient expression systems construction for various applications, as well as the enhancement strategies through promoter and codon optimization, “humanization” of glycosylation process, inhibition of gene silencing and protease activity, and also summarize the application of plant-derived protein products, which aim to provide a theoretical and application basis for the development of plant bioreactors.

Key words: Plant bioreactor Molecular pharming Heterologous proteins Transient and stable expression

收稿日期: 2022-07-30 出版日期: 2023-02-14

ZTFLH:

Q819

基金资助: *湖南省自然科学基金(2021JJ30340);国家自然科学基金(31670955);国家自然科学基金(42177392)

通讯作者: **吴川电子信箱:wuchuan@csu.edu.cn

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引用本文:

邹奇, 潘炜松, 邱健, 束文圣, 吴川. 植物生物反应器优化策略与最新应用^*[J]. 中国生物工程杂志, 2023, 43(1): 71-86.

ZOU Qi, PAN Wei-song, QIU Jian, SHU Wen-sheng, WU Chuan. Recent Advances in Optimization Strategies and Applications of Plant Bioreactors. China Biotechnology, 2023, 43(1): 71-86.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2207066 或 https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I1/71

图1 植物生物反应器构建过程及体系[78-79]

图2 植物生物反应器外源蛋白生产流程及优化策略[61-62]

产品	应用	宿主	临床试验阶段	来源
Covifenz^?	新冠病毒疫苗	烟草	获批上市	Medicago, Canada
胃脂肪酶	囊性纤维化、胰腺炎	玉米	II期临床	http://www.meristem.com
乳铁蛋白	胃肠感染	玉米	I期临床	http://www.meristem.com
PRX-102	法布里病	烟草细胞培养液	II期临床	https://clini caltrials.Gov
自体FL疫苗	非霍奇金淋巴瘤	烟草	I期临床	Icon Genetics GmbH, Germany
疫苗重组保护性抗原(PA83-FhCMB)	炭疽病	烟草	I期临床	FhCMB, USA
疫苗Pfs25病毒样颗粒	疟疾	烟草	I期临床	FhCMB, USA
药物(zmapp)	埃博拉病毒感染	烟草	I期临床和II期临床	LeafBio (NIAID), Canada
四价VLP	H1N1、H3N2和季节性乙型流感病毒感染	烟草	III期临床	Medicago, Canada
流感病毒(H1N1) HA	流感	烟草	I期临床	FhCMB, USA
RhinoRx	鼻病毒感染	烟草	II期临床	http://www.plant biote chnology.com
P2G12 IgG抗体	HIV感染	烟草	I期临床	University of Surrey, UK
LSBC scFVs	非霍奇金淋巴瘤	烟草	I期临床	McCormick et al., 2011^[122]
H7 VLP	H7N9大流行性流感病毒疫苗	烟草	I期临床	Medicago, Canada
H5-VLP + GLA-AF疫苗	甲型流感、H5N1亚型感染	烟草	I期临床	Medicago, Canada
H5-VLP	H5N1大流行性流感病毒疫苗	烟草	I期临床和II期临床	Medicago, Canada
H1 VLP	季节性流感	烟草	I期临床	Medicago, Canada
CaroRX人源化小鼠抗体	龋齿	烟草	II期临床	Ma et al., 1998^[123]
人血清白蛋白	维持血压	亚麻	临床前	Agragen (Cincinatti,OH,USA)
人α-半乳糖苷酶A	法布里病	苔藓	I期临床	Greenovation Biotech GmbH, Germany
重组乳铁蛋白	HIV患者抗感染治疗	水稻	II期临床	Jason Baker (MMRF), USA
霍乱弧菌CTB	霍乱	水稻	I期临床	Nochi et al., 2007^[124]
rhLactoferrin	治疗老年慢性炎症	水稻	II期临床	Johns Hopkins University, USA
重组人内因子	维生素B12不足	拟南芥	II期临床	https://clini caltr ials.gov
乙型肝炎病毒表面抗原	乙型肝炎	马铃薯	I期临床	Thanavala et al., 2005^[125]
诺沃克病毒CP	腹泻	马铃薯	I期临床早期	Tacket et al., 2004^[126]
产肠毒素大肠杆菌LT-B	腹泻	马铃薯	I期临床早期	Zhou et al., 2015^[127]
重组葡糖脑苷脂酶(prGCD)	戈谢病	胡萝卜细胞培养液	III期临床和FDA认证	University in Aarhus, Denmark
乙酰胆碱酯酶(PRX-105)	生化防御	胡萝卜细胞培养液	I期临床	Protalix
产品	应用	宿主	临床试验阶段	来源
抗肿瘤坏死因子(Pr-anti-TNF)	关节炎	胡萝卜细胞培养液	临床前	Protalix
胰岛素(SBS-1000)	糖尿病	红花	I期临床和II期临床	Markley et al., 2006
Apo-A1Milano	心血管疾病	红花	临床前	http://www.sembi osys.com
重组血纤维蛋白溶酶(BLX-155)	血栓预防	浮萍属 (莴苣)	临床前	Biolex therapeutics (Pittsboro, NC, USA)
乳铁蛋白	抗丙肝病毒感染治疗	浮萍属 (莴苣)	I期临床和II期临床	Biolex Therapeutics, USA
改良α-干扰素(locteron R)	丙型肝炎	浮萍属 (莴苣)	II期临床	Biolex therapeutics (Pittsboro, NC, USA)
Anti-CD20单克隆抗体(BLX-301)	非霍奇金淋巴瘤	浮萍属 (莴苣)	临床前	Biolex therapeutics (Pittsboro, NC, USA)
狂犬病病毒GP/NP	狂犬病	菠菜	I期临床早期	Yusibov et al., 2002^[128]

表1 植物生物反应器生产医药产品及临床试验阶段[62,79]

表2 植物生物反应器生产相关功能性食品[129]

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