Bioprocess biomarker identification and diagnosis for industrial mAb production based on metabolic profiling and multivariate data analysis.

IF 3.5 3区 生物学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Bioprocess and Biosystems Engineering Pub Date : 2025-05-01 Epub Date: 2025-03-10 DOI:10.1007/s00449-025-03142-4
Yingting Shi, Yuxiang Wan, Jiayu Yang, Yuting Lu, Xinyuan Xie, Jianyang Pan, Haibin Wang, Haibin Qu
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引用次数: 0

Abstract

Monoclonal antibody (mAb) production is a complex bioprocess influenced by various cellular and metabolic factors. Understanding these interactions is critical for optimizing manufacturing and improving yields. In this study, we proposed a diagnostic and identification strategy using quantitative proton nuclear magnetic resonance (1H qNMR) technology-based pharmaceutical process-omics to analyze bioprocess variability and unveil significant metabolites affecting cell growth and yield during industrial mAb manufacturing. First, batch level model (BLM) and orthogonal partial least squares-discriminant analysis (OPLS-DA) identified glucose and lactate as primary contributors to culture run variability. Maintaining an optimal glucose set point was crucial for high-yield runs. Second, a partial least squares (PLS) regression model was established, which revealed viable cell density (VCD), along with glutamine, maltose, tyrosine, citrate, methionine, and lactate, as critical variables impacting mAb yield. Finally, hierarchical clustering analysis (HCA) highlighted one-carbon metabolism metabolites, such as choline, pyroglutamate, and formate, as closely associated with VCD. These findings provide a foundation for future bioprocess optimization through cell line engineering and media formulation adjustments, ultimately enhancing mAb production efficiency.

基于代谢谱和多变量数据分析的工业单抗生产的生物过程生物标志物鉴定和诊断。
单克隆抗体(mAb)的产生是一个复杂的生物过程,受多种细胞和代谢因素的影响。了解这些相互作用对于优化制造和提高产量至关重要。在这项研究中,我们提出了一种基于定量质子核磁共振(1H qNMR)技术的制药过程组学诊断和鉴定策略,以分析生物过程变异性,并揭示影响工业单抗生产过程中细胞生长和产量的重要代谢物。首先,批水平模型(BLM)和正交偏最小二乘判别分析(OPLS-DA)确定葡萄糖和乳酸是影响培养运行变异性的主要因素。维持最佳葡萄糖设定点对于高产量运行至关重要。其次,建立了偏最小二乘(PLS)回归模型,发现活细胞密度(VCD)以及谷氨酰胺、麦芽糖、酪氨酸、柠檬酸盐、蛋氨酸和乳酸盐是影响单抗产量的关键变量。最后,层次聚类分析(HCA)强调了胆碱、焦谷氨酸和甲酸盐等单碳代谢代谢物与VCD密切相关。这些发现为未来通过细胞系工程和培养基配方调整来优化生物工艺奠定了基础,最终提高单克隆抗体的生产效率。
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来源期刊
Bioprocess and Biosystems Engineering
Bioprocess and Biosystems Engineering 工程技术-工程:化工
CiteScore
7.90
自引率
2.60%
发文量
147
审稿时长
2.6 months
期刊介绍: Bioprocess and Biosystems Engineering provides an international peer-reviewed forum to facilitate the discussion between engineering and biological science to find efficient solutions in the development and improvement of bioprocesses. The aim of the journal is to focus more attention on the multidisciplinary approaches for integrative bioprocess design. Of special interest are the rational manipulation of biosystems through metabolic engineering techniques to provide new biocatalysts as well as the model based design of bioprocesses (up-stream processing, bioreactor operation and downstream processing) that will lead to new and sustainable production processes. Contributions are targeted at new approaches for rational and evolutive design of cellular systems by taking into account the environment and constraints of technical production processes, integration of recombinant technology and process design, as well as new hybrid intersections such as bioinformatics and process systems engineering. Manuscripts concerning the design, simulation, experimental validation, control, and economic as well as ecological evaluation of novel processes using biosystems or parts thereof (e.g., enzymes, microorganisms, mammalian cells, plant cells, or tissue), their related products, or technical devices are also encouraged. The Editors will consider papers for publication based on novelty, their impact on biotechnological production and their contribution to the advancement of bioprocess and biosystems engineering science. Submission of papers dealing with routine aspects of bioprocess engineering (e.g., routine application of established methodologies, and description of established equipment) are discouraged.
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