合成生物学 ›› 2021, Vol. 2 ›› Issue (4): 482-496.DOI: 10.12211/2096-8280.2021-051
谢良志1,2
收稿日期:
2021-04-26
修回日期:
2021-08-02
出版日期:
2021-09-10
发布日期:
2021-09-10
作者简介:
Liangzhi XIE1,2
Received:
2021-04-26
Revised:
2021-08-02
Online:
2021-09-10
Published:
2021-09-10
摘要:
以单克隆抗体药物及重组蛋白为代表的生物药在肿瘤、自身免疫性疾病、病毒感染等多个重大疾病的预防及治疗领域发挥了重要作用,已成为全球制药行业的主攻方向之一。动物细胞培养技术和工艺放大是生物药产业化的核心技术,存在巨大挑战,在20世纪90年代初仍被认为是一个很难破解的“黑箱”,是制约行业发展的关键瓶颈之一。自60年代开始,王义翘教授领导的实验室和美国麻省理工学院生物技术工程中心(Biotechnology Process Engineering Center, MIT-BPEC)对动物细胞培养技术进行了全方位系统的研究和探索,涵盖了从贴壁细胞的微载体培养到CHO细胞的无血清悬浮培养,从批次培养、连续培养、灌流培养到高密度流加培养过程中的关键技术和工程问题,包括细胞代谢有毒副产品的控制、高密度流加培养工艺的过程控制、蛋白质糖基化多样性质量分析和控制、搅拌和鼓泡导致的细胞损伤等关键瓶颈。王义翘教授团队数十年的前瞻性研究和多学科交叉合作在动物细胞代谢调控、数十种营养物质的化学计量平衡配比、无血清培养基的开发、有毒代谢副产物的控制、大分子生物药的糖基化多样性分析和质量控制、生物反应器的设计和工艺放大等一系列关键技术的研发方面取得了突破性的前沿成果,为90年代后高密度流加培养工艺在生物技术产品大规模商业化生产中的广泛应用奠定了坚实的基础,为推动全球生物制药技术和产品的蓬勃发展做出了不可磨灭的伟大贡献。本文作者结合90年代初期在王义翘教授实验室学习期间的亲身经历,试图从自己熟悉的专业领域总结王教授团队在生物药产业化起步阶段针对动物细胞培养的关键技术攻关方面取得的重要成果,从一个侧面概述王教授1965—1995三十年间所开展的前沿性研究对全球生物制药此后近30年来的蓬勃发展所做出的奠基性工作和杰出贡献。谨以此文致敬和缅怀恩师王义翘教授!
中图分类号:
谢良志. 生物药产业蓬勃发展早期的奠基性系统开发——缅怀王义翘教授的开创性研究和成就[J]. 合成生物学, 2021, 2(4): 482-496.
Liangzhi XIE. Contributions to the booming biologics industrialization —a dedicated pioneer: Professor. Daniel I. C. Wang[J]. Synthetic Biology Journal, 2021, 2(4): 482-496.
图2 化学计量平衡和加料控制的流加培养工艺中活细胞密度与批次培养对比
Fig. 2 Comparison of the viable cell density in the perfusion culture developed on stoichiometric balance and feed control to that observed in the batch process
图3 化学计量平衡和加料控制的流加培养工艺中抗体产量与批次培养对比
Fig. 3 Comparison of the antibody yield in the perfusion culture developed on stoichiometric balance and feed control with that of the batch process
图4 化学计量平衡和加料控制的流加培养工艺中葡萄糖控制情况与批次培养对比
Fig. 4 Comparison of the glucose control index of the perfusion culture developed on stoichiometric balance and feed control with that of the batch process
图5 化学计量平衡和加料控制的流加培养工艺中谷氨酰胺控制情况与批次培养对比
Fig. 5 Comparison of the glutamine control for the perfusion culture developed on stoichiometric balance and feed control with that of the batch process
图6 化学计量平衡和加料控制的流加培养工艺中副产物乳酸和氨产生速率与批次培养对比
Fig. 6 Comparison of the byproduct lactic acid and ammonia production for the perfusion developed on stoichiometric balance and feed control with those of the batch process
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