Rational development of fed-batch mammalian cell culture processes

哺乳动物细胞培养仍然是制造临床应用重组蛋白的主要表达系统。随着数百种蛋白质产品目前正在进行临床试验，以及预计将出现几种轰动一时的生物仿制药，生物疗法市场预计将在未来十年内呈指数级增长。对于这些新型生物产品中的大多数，以经济高效的方式大规模生产它们的能力将是它们成功转化为临床和市场的关键因素。 NSERC发现研究计划的中心目标是设计创新战略，使基于细胞培养的制造过程能够快速发展，并具有成本效益。为了更好地应对哺乳动物细胞培养固有的复杂性，这项研究将按照多尺度系统的方法进行，在细胞和过程水平上整合信息。更具体地说，该研究计划的目标将是：i)在相关工艺条件下对哺乳动物细胞进行全面的代谢表征，以指导和简化优化工作；ii)开发可靠的数学模型，将工艺条件和细胞培养状态联系起来，以模拟和预测工艺性能；iii)设计和实施高效的基于模型的动态补料批次策略，以确保产品的高产量和一致性。 该方法将以先进和新兴的分析方法为基础，包括使用质谱分析和同位素示踪剂进行代谢研究，以及使用表面等离子体共振(SPR)对产品生物活性进行快速在线评估。这项研究将主要针对一个与工业相关的应用，即利用中国仓鼠卵巢(CHO)细胞生产克隆抗体，因为这些细胞是生物制药行业的主要主力。这项研究还将继续开发涉及哺乳动物细胞的细胞培养过程，这些细胞经过改造后具有更高的代谢效率。 该研究项目的新颖性不仅在于其预期的结果，还在于创新地应用了多尺度系统方法，将细胞和过程工程策略相结合，以进行合理的过程开发和产生新的知识。这项研究预计将为生物疗法的开发和制造带来重大贡献，生物疗法是一个具有相当重要经济意义的领域，对加拿大公民的健康和福利有直接影响。通过满足对改进和高效生物过程的需求，这些研究工作可以帮助减少将重组产品推向临床和市场的成本和时间，从而最终使患者和行业都受益。

Mammalian cell culture remains the dominant expression system for the manufacturing of recombinant proteins for clinical applications. With several hundreds of protein products currently in clinical trials and with the anticipated emergence of several blockbuster biosimilars, the biotherapeutics market is expected to grow exponentially within the next decade. For the majority of these novel bioproducts, the capacity to mass produce them in a cost-efficient manner will be a critical factor for their successful translation to the clinic and market. The central goal of this NSERC Discovery Research Program is to devise innovative strategies that will enable the rapid development of robust and cost-effective cell culture-based manufacturing processes. To better cope with the inherent complexity of mammalian cell cultures, the research will be conducted following a multi-scale system's approach integrating information at the cellular and process levels. More specifically, the research program will aim to i) conduct comprehensive metabolic characterization of mammalian cells under relevant process conditions in order to guide and streamline optimization efforts ii) develop reliable mathematical models linking process conditions and cell culture state in order to simulate and predict process performance and iii) design and implement efficient model-based dynamic fed-batch strategies ensuring high product yield and consistency. The methodology will be based on advanced and emerging analytical methods, including the use of mass spectrometry analysis and isotopic tracers for conducting metabolic studies and surface plasmon resonance (SPR) for rapid at-line assessment of product bioactivity. The research will primarily target an industrially relevant application, the production of monoclonal antibodies by Chinese Hamster Ovary (CHO) cells, as these cells are the main workhorse of the biopharmaceutical industry. The research will also pursue the development of cell culture processes involving mammalian cells that have been engineered to possess an improved metabolic efficiency. The novelty of the research program lies not only in its anticipated outcomes, but also in the innovative application of a multi-scale systems approach combining cellular and process engineering strategies for conducting rational process development and generating new knowledge. This research is expected to bring a significant contribution to the development and manufacturing of biotherapeutics, an area of considerable economic importance and having a direct impact on the health and welfare of Canadian citizens. By addressing the needs for improved and efficient bioprocesses, these research efforts can help to reduce the cost and time in getting recombinant products to the clinic and market and will thus ultimately benefit both patients and industry.