Model-driven Media Optimization in Hybridoma Cell Line

描述（由申请人提供）：项目摘要/摘要：基于蛋白质的治疗方法对医疗保健做出了巨大贡献，并在总药物中占很大比例且不断增长。目前，大多数生物制药产品都是使用哺乳动物细胞系生产的。然而，与微生物系统相比，哺乳动物细胞培养物中的生产率和产物滴度低，主要是由于标准哺乳动物细胞培养物中可实现的低生物质浓度。此外，哺乳动物细胞系产生大量的废物，如乳酸盐、丙氨酸和氨，这降低了生物质产量和蛋白质产量，引起毒性适应，并抑制细胞生长。目前，哺乳动物细胞培养中的培养基和工艺优化策略是使用试错法进行的，其中通过实验费力地改进工艺输出。这些经验优化技术被广泛使用，因为在大多数情况下，对影响宿主细胞系中生长和蛋白质产生的潜在生理相互作用知之甚少。对细胞系生理学和代谢的基本理解可以大大改善和加速哺乳动物细胞系系统中的培养基和工艺开发。培养基优化和工艺开发中的合理设计方法需要能够捕获和分析宿主细胞系的潜在生理学的建模和模拟技术。在这个SBIR研究计划中，我们打算使用鼠杂交瘤细胞系的重建模型来证明代谢建模在培养基优化中的价值。结合我们的建模技术，并使用重建的杂交瘤代谢模型，我们将设计硅衍生的培养基配方，减少杂交瘤细胞培养中的副产物形成，并随后使用实验测量评估我们的培养基设计。该提案的成功将证明通过合理选择营养补充策略，以模型为驱动改进重组蛋白生产的科学和技术可行性，并最终降低治疗性蛋白质开发和制造的成本，以确保下一代药物的数量足以满足患者的需求，并且价格足够低，患者可以负担得起。项目叙述：基于蛋白质的治疗剂对医疗保健做出了巨大贡献，并在药物总量中占很大且不断增长的比例。该提案的成功将证明通过合理选择营养补充策略，以模型为驱动改进重组蛋白生产的科学和技术可行性，并最终降低治疗性蛋白质开发和制造的成本，以确保下一代药物的数量足以满足患者的需求，并且价格足够低，患者可以负担得起。

DESCRIPTION (provided by applicant): Project Summary/Abstract: Protein-based therapeutics have contributed immensely to health care and constitute a large and growing percentage of the total pharmaceutical drugs. The majority of the biopharmaceutical products are currently manufactured using mammalian cell lines. However, compared to microbial systems, productivity and product titers in mammalian cell cultures are low mainly due to the low biomass concentration achievable in standard mammalian cell culture. In addition, mammalian cell lines produce significant amounts of waste products such as lactate, alanine, and ammonia, which reduce biomass yield and protein production, cause toxic accommodation, and inhibit cell growth. Currently, media and process optimization strategies in mammalian cell culture are performed using a trial and error approach where process outputs are improved laboriously by experimentation. These empirical optimization techniques are widely used because in most cases little is known about the underlying physiological interactions that impact growth and protein production in the host cell lines. A fundamental understanding of cell line physiology and metabolism can greatly improve and accelerate media and process development in mammalian cell line systems. A rational design approach in media optimization and process development requires modeling and simulation technologies capable of capturing and analyzing the underlying physiology of the host cell line. In this SBIR research plan, we intend to demonstrate the value of metabolic modeling in media optimization using a reconstructed model of murine hybridoma cell line. In combination with our modeling technology and using the reconstructed model of hybridoma metabolism, we will design in silico-derived media formulations that reduce byproduct formation in hybridoma cell culture and subsequently evaluate our media designs using experimental measurements. Success of this proposal will demonstrate the scientific and technical feasibility of model-driven improvements in recombinant protein production through the rational selection of nutrient supplementation strategies and ultimately reduce the cost of therapeutic protein development and manufacturing to ensure that the next generation of medicines can be created in amounts large enough to meet patients' needs, and at a price low enough that patients can afford. Project Narrative: Protein-based therapeutics have contributed immensely to health care and constitute a large and growing percentage of the total pharmaceutical drugs. Success of this proposal will demonstrate the scientific and technical feasibility of model-driven improvements in recombinant protein production through the rational selection of nutrient supplementation strategies and ultimately reduce the cost of therapeutic protein development and manufacturing to ensure that the next generation of medicines can be created in amounts large enough to meet patients' needs, and at a price low enough that patients can afford.