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首页> 外文期刊>Biotechnology Progress >Perfusion process combining low temperature and valeric acid for enhanced recombinant factor VIII production
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Perfusion process combining low temperature and valeric acid for enhanced recombinant factor VIII production

机译：结合低温和valeric酸的灌注过程进行增强重组因子VIII生产

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Perfusion operation mode remains the preferred platform for production of labile biopharmaceuticals (e.g., blood factors) and is also being increasingly adopted for production of stable products (e.g., monoclonal antibodies). Regardless of the product, process development typically aims at maximizing production capacity. In this work, we investigated the impact of perfusion cultivation conditions on process productivity for production of human factor VIII (FVIII). Recombinant CHO cells were cultivated in bioreactors coupled to inclined settlers and the effects of reducing the temperature to 31 degrees C with or without valeric acid (VA) supplementation were evaluated. Increases in cell specific productivity (q(p)) up to 2.4-fold (FVIII concentration) and up to 3.0-fold (FVIII biological activity) were obtained at 31 degrees C with VA compared to the control at 37 degrees C. Biological activity is the most important quality attribute for FVIII and was positively affected by mild hypothermia in combination with the chemical inducer. The low temperature conditions resulted in enhanced product transcript levels, suggesting that the higher q(p) is related to the increased mRNA levels. Furthermore, a high-producer subclone was evaluated under the perfusion conditions optimized for the parental clone (31 degrees C with VA), yielding increases in q(p) of 6-fold and 15-fold compared to the parental clone cultivated under the same condition and at 37 degrees C, respectively. The proposed perfusion strategy enables increased product formation without increasing production costs, being potentially applicable to perfusion production of other CHO-derived biopharmaceuticals. To the best of our knowledge, this is the first report showing the benefits of perfusion combining mild hypothermia with VA supplementation.
机译：灌注操作模式仍然是用于生产不稳定生物制药（例如，血液因子）的优选平台，并且越来越多地用于生产稳定产品（例如单克隆抗体）。无论产品如何，过程开发通常都旨在最大化生产能力。在这项工作中，我们研究了灌注栽培条件对人类因子VIII（FVIII）生产过程生产率的影响。在偶联沉降器的生物反应器中培养重组CHO细胞，并评估将温度降低至31℃的效果或不含戊酸（VA）补充。在31摄氏度的31℃下，在31℃下，在31℃下，将细胞比生产率的增加（Q（P））增加到2.4倍（FVIII浓度）和高达3.0倍（FVIII生物活性），与37摄氏度的对照相比，生物活性是FVIII最重要的质量属性，并与化学诱导剂结合使用温和的体温过低影响。低温条件导致增强的产品转录水平，表明较高的Q（P）与增加的mRNA水平有关。此外，在针对亲本克隆的灌注条件下评价高生产区亚克隆（31摄氏度），与在相同下栽培的亲本克隆相比，Q（P）的Q（P）的增加率为15倍条件和37摄氏度。所提出的灌注策略使得能够增加产品形成而不增加生产成本，可能适用于灌注其他Cho衍生的生物药物的生产。据我们所知，这是第一个报告，表明灌注与VA补充的灌注肥无力的好处。

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