Characterization, modeling and environmental manipulation of mammalian cell culture systems for optimal protein production

哺乳动物细胞培养包括用于生产许多高价值生物药物的主要平台，所述高价值生物药物包括酶、单克隆抗体（MAb）、病毒疫苗、激素和免疫调节剂。生物制药行业的未来将依赖于这些哺乳动物细胞培养生产系统的开发和增强。由于所需的高度专业化的培养条件以及培养物对由于培养条件的轻微变化而导致的生产率降低或显著细胞死亡的敏感性，此类生物制剂以相对小的量生产。虽然早期的几代生物化学工程师专注于生产的非生物方面，如反应器设计，但最近的工程发展已经认识到，提高产量的最大潜力在于动物细胞本身。该建议涉及开发用于通过哺乳动物细胞生产治疗性蛋白质的新型优化策略。这个问题将通过仔细的建模和实验来解决，包括温度，代谢物和代谢途径，生物反应器操作模式的操作，以及通过所考虑的生物体的细胞周期的遍历速率。一个重要的目标是培养研究生谁是精通的生物和数学方面的生物过程optimization.Finally，所提出的工作的目标是开发一个强大的策略，哺乳动物细胞为基础的治疗性蛋白质加工系统的设计，包括媒体设计，生物反应器的操作条件和操作模式。所使用的一般策略可以被定义为宏观尺度的代谢工程与细胞水平的建模相结合。高度可重复的动物细胞培养系统的开发将对生物制药行业以外的许多生物工业应用产生重大影响。

Mammalian cell culture comprises a major platform for producing a number of high-value biopharmaceuticals, including enzymes, monoclonal antibodies (MAbs), viral vaccines, hormones and immuno-regulators. The future of the biopharmaceutical industry will rely on the development and enhancement of these mammalian cell culture production systems. Such biologics are produced in relatively small quantities due to the highly specialized culture conditions needed and the susceptibility of the culture to either reduced productivity or significant cell death as a result of slight changes in culture conditions. While earlier generations of biochemical engineers focused on the non-biological aspects of production, such as reactor design, more recent engineering developments have recognized that the greatest potential for enhancing production lies within the animal cells themselves.In this proposal, an important and often neglected aspect of bioprocess development, namely bioprocess optimization is addressed. This proposal deals with the development of a novel optimization strategy for production of therapeutic proteins by mammalian cells. The problem will be addressed by careful modeling and experiments including the manipulation of temperature, metabolites and metabolic pathways, bioreactor operating mode, and rate of traverse through the cell cycle of the organism under consideration. An important goal is the training of graduate students who are well versed in both the biological and the mathematical aspects of bioprocess optimization.Ultimately, the objective of the proposed work is to develop a robust strategy for the design of mammalian cell based therapeutic protein processing systems, including media design, bioreactor operation conditions and operating mode. The general strategy to be used can be defined as macro-scale metabolic engineering combined with modeling at the cellular level. The development of highly reproducible animal cell culture systems will have significant impact for many bioindustrial applications beyond the biopharma industry.