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A systematic approach combining process optimization and clinically-relevant quality attributes to manufacture high potency mesenchymal stromal cells for clinical and veterinary applications

一种系统方法，结合工艺优化和临床相关质量属性，制造用于临床和兽医应用的高效间充质基质细胞

基本信息

批准号：
RGPIN-2018-05737
负责人：
Viswanathan, Sowmya
金额：
$ 4.08万
依托单位：
University of Toronto
依托单位国家：
加拿大
项目类别：
Discovery Grants Program - Individual
财政年份：
2022
资助国家：
加拿大
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746055
关键词：
systematic approach combining process optimization

项目摘要

Problem Although advances in bioreactor technology allow for scalable manufacturing of mesenchymal stromal cells (MSCs), many of these methods are borrowed from the vaccine and antibody industry, and do not prioritize cell functionality. Commercial-scale expansion of MSCs contributed to sub-optimal performance in late-phase trials for multiple companies. Enhanced manufacturing methods that produce scaleable and fuctional MSCs are needed to capitalize on the substantial investment in MSCs. Solution My lab has filed a patent to manufacture scalable 3D MSCs with enhanced anti-inflammatory properties. Using a statistically-based approach, we will systematically optimize bioprocess parameters to manufacture sufficient quantities and quality of therapeutically-relevant MSCs with enhanced anti-inflammatory properties, without increasing costs. First, using iterative Design of Experiment (DoE) and high throughput read-outs, combinations of bioprocess parameters will be modeled and tested for their relative impact on MSC yield, anti-inflammatory factors and cost. Additional processing parameters that affect the metabolic profile of the MSC cultures will be investigated and queried to further optimize combination of bioprocess parameters. Human and canine MSCs will be manufactured in large scales, and tested in domestic dogs with inflammatory disease to validate this approach to optimize bioprocess parameters. O1 Statistical modeling to optimize process parameters that simultaneously improve MSC yield and anti-inflammatory attributes Herein, we use Definitive Screening Designs (DSD) to model the effects of various permutations of bioprocess parameters on MSC yield, potency and calculated cost. A response surface map allows hierarchical clustering of combination of bioprocess parameters that maximize cell yield and potency at low costs. O2 Assess metabolic parameters read-outs to further optimize MSC bioprocess parameters Optimizing metabolic parameters and changes in MSC size and cellular structures will be conducted in this objective using Raman spectroscopy. These parameters can subsequently be monitored on-line in MSC manufacturing vessels providing feedback to rapidly “correct” process parameters in situ.O3 Validate scalability and therapeutic potency of MSCs in veterinary applications Human and canine MSCs will be manufactured in 1L scales using the optimized combination of bioprocess parameters. Canine AT-MSCs will be tested in domestic dogs with joint diseases.Significance The process optimization will result in large scale manufacturing of therapeutically-potent MSCs for effective clinical and veterinary applications in inflammatory diseases. This program offers training opportunities in statistical modeling, bioprocess optimization, cell manufacturing, and veterinary application for HQPs.

尽管生物反应器技术的进步允许间充质基质细胞（MSC）的可规模化制造，但这些方法中的许多都是从疫苗和抗体行业借来的，并且没有优先考虑细胞功能。MSC的商业规模扩张导致多家公司在后期试验中表现不佳。需要生产可规模化和功能性MSC的增强的制造方法来利用MSC的大量投资。解决方案我的实验室已经申请了一项专利，用于制造具有增强抗炎特性的可扩展3D MSC。使用基于药理学的方法，我们将系统地优化生物工艺参数，以生产足够数量和质量的具有增强抗炎特性的治疗相关MSC，而不会增加成本。首先，使用迭代实验设计（DoE）和高通量读数，将对生物过程参数的组合进行建模并测试其对MSC产量、抗炎因子和成本的相对影响。将对影响MSC培养物代谢特征的其他工艺参数进行研究和查询，以进一步优化生物工艺参数的组合。人类和犬MSC将大规模生产，并在患有炎症性疾病的家犬中进行测试，以验证这种优化生物工艺参数的方法。O 1统计建模以优化同时提高MSC产量和抗炎属性的工艺参数在此，我们使用连续筛选设计（DSD）来模拟生物工艺参数的各种排列对MSC产量、效力和计算成本的影响。响应面图允许生物过程参数的组合的分级聚类，其以低成本最大化细胞产率和效力。O2评估代谢参数读数，以进一步优化MSC生物工艺参数优化代谢参数和MSC大小和细胞结构的变化将在本目标中使用拉曼光谱进行。这些参数随后可以在MSC制造容器中在线监测，提供反馈以快速“校正”原位过程参数。MSC在兽医应用中的O3浓度可扩展性和治疗效力人和犬MSC将使用生物过程参数的优化组合以1 L规模制造。犬AT-MSCs将在患有关节疾病的家犬中进行测试。意义该工艺优化将导致大规模生产具有治疗效力的MSCs，用于炎症性疾病的有效临床和兽医应用。该计划提供统计建模，生物过程优化，细胞制造和兽医应用HQP的培训机会。