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

谢良志

doi:10.12211/2096-8280.2021-051

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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

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- 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
- Contributions to the booming biologics industrialization —a dedicated pioneer： Professor. Daniel I. C. Wang
- 合成生物学 2021年2卷第4期页码：482-496
- 作者机构：
  
  1.北京市蛋白和抗体研发及制备工程技术研究中心，北京神州细胞生物技术集团股份公司，北京　100176
  2.单克隆抗体上游研发技术北京市重点实验室，北京义翘神州科技股份有限公司，北京　100176
- 作者简介：
  
  [ "谢良志（1966—），男，博士，教授，主要从事生物化工、动物细胞培养、大分子生物药、基因工程疫苗、抗病毒中和抗体药物研发、临床研究和大规模生产及管理。E-mail：liangzhi@yahoo.com" ]
- 基金信息：
- DOI：10.12211/2096-8280.2021-051
  中图分类号： Q81
- 收稿：2021-04-26，
  
  修回：2021-08-02，
  
  纸质出版：2021-08-31
- 稿件说明：
移动端阅览
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

XIE Liangzhi. Contributions to the booming biologics industrialization—a dedicated pioneer： Professor. Daniel I. C. Wang［J］. Synthetic Biology Journal， 2021， 2（4）： 482-496
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 DOI： 10.12211/2096-8280.2021-051.

XIE Liangzhi. Contributions to the booming biologics industrialization—a dedicated pioneer： Professor. Daniel I. C. Wang［J］. Synthetic Biology Journal， 2021， 2（4）： 482-496 DOI： 10.12211/2096-8280.2021-051.

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！

Abstract

Biologics including monoclonal antibodies and recombinant proteins have made significant impacts on the prevention and treatment of many important diseases

such as cancer

autoimmune disease and viral infections. Mammalian cell culture is a key but full-of-challenging technology for large-scale manufacturing of these high-demand and life-saving biologics. Until the early nineties

mammalian cell culture process was largely deemed as an unsolvable black box

and cell culture process scale-up was a significant challenge. As a result

mammalian cell culture process was an essential and key but bottle-neck technology for the development and manufacturing of biologics at that time. Prof. Daniel I.C. Wang

a pioneer in industrial biotechnology and founding director of MIT's Biotechnology Process Engineering Center

took the initiatives in the late 1960's to systematical study on all spectra of problems related to mammalian cell culture and its application in industrial biologics production. His research interests spanned from the microcarrier culture of adherent cells to the serum-free culture of suspension-adapted CHO cells; from batch culture

continuous culture

perfusion culture

air-lift fiber-bed culture to high-density fed-batch culture; from process technologies to engineering challenges. Several decades of Prof. Wang's leading role in the cutting-edge research and cross-discipline collaboration made significant breakthroughs in cell metabolism control

stoichiometrically-balanced culture medium and feed supplement design

serum-free medium development

inhibitory by-product control

protein glycosylation heterogeneity monitoring and control

on-line monitoring of bioreactor and cell culture process scale-up. Prof. Wang's achievements greatly advanced knowledge and understanding of the cell culture process and laid a solid foundation for the subsequent development and wide application of these novel technologies

especially the fed-batch culture process

in the commercial manufacturing of life-saving biological products and facilitated the booming of the biotech industry in the recent decades. This review article is dedicated in memorial of my Sc.D. thesis advisor Prof. Daniel. I.C. Wang!

关键词

Keywords

references

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