Pennington Oliver, Espinel Ríos Sebastián, Sebastian Mauro Torres, Dickson Alan, Zhang Dongda
University of Manchester, Manchester, Oxford Road, M1 3AL, UK.
Princeton University, New Jersey, NJ, 08544, USA.
Metab Eng. 2024 Nov;86:274-287. doi: 10.1016/j.ymben.2024.10.013. Epub 2024 Oct 29.
Mammalian cell cultures make a significant contribution to the pharmaceutical industry. They produce many of the biopharmaceuticals obtaining FDA-approval each year. Motivated by quality-by-design principles, various modelling methodologies are frequently trialled to gain insight into these bioprocesses. However, these systems are highly complex and uncertain, involving dynamics at different scales, both in time and space, making them challenging to model in a comprehensive and fully mechanistic manner. This study develops a machine-learning-supported multiscale modelling framework of cell cultures, linking the macroscale bioprocess dynamics to the microscale metabolic flux distribution. As a relevant biopharmaceutical case study, we consider the production of Trastuzumab by Chinese Hamster Ovary (CHO) cells in batch. A macroscale hybrid model is constructed by integrating macro-kinetic and machine-learning approaches. Enzyme-constrained Dynamic Metabolic Flux Analysis (ecDMFA) is adopted to calculate flux distributions based on the dynamic predictions of the hybrid model. Uncertainty estimation of the multiscale model is conducted through bootstrapping. Judging from experimental data, our hybrid model can reduce the modelling error of the macroscale dynamics to 8.0%; a 70% reduction from the purely mechanistic model. In addition, the predicted dynamic flux distribution aligns with observations seen in literature, highlighting important metabolic changes throughout the process. Model uncertainty is maintained at a low level, demonstrating the trustworthiness of the predictions. Overall, our comprehensive modelling framework has the potential to facilitate the development of digital twins in the biopharmaceutical industry.
哺乳动物细胞培养对制药行业做出了重大贡献。它们生产了每年获得美国食品药品监督管理局(FDA)批准的许多生物制药产品。受质量源于设计原则的推动,人们经常尝试各种建模方法来深入了解这些生物过程。然而,这些系统高度复杂且具有不确定性,涉及不同时间和空间尺度上的动态变化,这使得以全面且完全基于机理的方式对其进行建模具有挑战性。本研究开发了一种机器学习支持的细胞培养多尺度建模框架,将宏观生物过程动态与微观代谢通量分布联系起来。作为一个相关的生物制药案例研究,我们考虑中国仓鼠卵巢(CHO)细胞分批生产曲妥珠单抗的过程。通过整合宏观动力学和机器学习方法构建了一个宏观混合模型。采用酶约束动态代谢通量分析(ecDMFA)根据混合模型的动态预测来计算通量分布。通过自助法对多尺度模型进行不确定性估计。从实验数据来看,我们的混合模型可以将宏观动力学的建模误差降低到8.0%;比纯机理模型降低了70%。此外,预测的动态通量分布与文献中观察到的结果一致,突出了整个过程中重要的代谢变化。模型不确定性保持在较低水平,证明了预测的可信度。总体而言,我们的综合建模框架有潜力促进生物制药行业数字孪生体的发展。