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首页> 外文期刊>Biotechnology Progress >Identifying a robust design space for glycosylation during monoclonal antibody production
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Identifying a robust design space for glycosylation during monoclonal antibody production

机译：确定单克隆抗体生产过程中糖基化的强大设计空间

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Glycan distribution has been identified as a critical quality attribute for many biopharmaceutical products, including monoclonal antibodies. Consequently, determining quantitatively how process variables affect glycan distribution is important during process development to control antibody glycosylation. In this work, we assess the effect of six bioreactor process variables on the glycan distribution of an IgG1 produced in CHO cells. Our analysis established that glucose and glutamine media concentration, temperature, pH, agitation rate, and dissolved oxygen (DO) had small but significant effects on the relative percentage of various glycans. In addition, we assessed glycosylation enzyme transcript levels and intracellular sugar nucleotide concentrations within the CHO cells to provide a biological explanation for the observed effects on glycan distributions. From these results we identified a robust operating region, or design space, in which the IgG1 could be produced with a consistent glycan distribution. Since our results indicate that perturbations to bioreactor process variables will cause only small (even if significant) changes to the relative percentage of various glycans (<+/- 1.5%)changes that are too small to affect the bioactivity and efficacy of this IgG1 significantlyit follows that the glycan distribution obtained will be consistent even with relatively large variations in bioreactor process variables. However, for therapeutic proteins where bioactivity and efficacy are affected by small changes to the relative percentage of glycans, the same analysis would identify the manipulated variables capable of changing glycan distribution, and hence can be used to implement a glycosylation control strategy. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1149-1162, 2016
机译：聚糖的分布已被确定为许多生物制药产品（包括单克隆抗体）的关键质量属性。因此，定量确定过程变量如何影响聚糖分布对于控制抗体糖基化的过程开发至关重要。在这项工作中，我们评估了六个生物反应器过程变量对CHO细胞中产生的IgG1的聚糖分布的影响。我们的分析确定，葡萄糖和谷氨酰胺培养基的浓度，温度，pH，搅拌速率和溶解氧（DO）对各种聚糖的相对百分比影响很小，但影响很大。此外，我们评估了CHO细胞内的糖基化酶转录水平和细胞内糖核苷酸浓度，为观察到的对聚糖分布的影响提供了生物学解释。根据这些结果，我们确定了一个可靠的操作区域或设计空间，可在其中产生具有一致的聚糖分布的IgG1。由于我们的结果表明，对生物反应器过程变量的扰动只会导致各种聚糖的相对百分比的微小变化（即使显着变化）（<+/- 1.5％），这些变化太小而不会显着影响该IgG1的生物活性和功效。由此得出结论，即使生物反应器工艺变量的变化较大，获得的聚糖分布也将保持一致。但是，对于生物活性和功效受聚糖相对百分比的微小变化影响的治疗性蛋白质，相同的分析将确定能够改变聚糖分布的操纵变量，因此可用于实施糖基化控制策略。 （c）2016美国化学工程师学会生物技术学会。 Prog。，32：1149-1162，2016

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