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铁原料及其杂质对 CHO 代谢和重组蛋白产品质量的影响。

Impact of iron raw materials and their impurities on CHO metabolism and recombinant protein product quality.

机构信息

Merck Life Science, Upstream R&D, Darmstadt, Germany.

Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Darmstadt, Germany.

出版信息

Biotechnol Prog. 2021 Jul;37(4):e3148. doi: 10.1002/btpr.3148. Epub 2021 May 3.

DOI:10.1002/btpr.3148
PMID:33742789
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8459231/
Abstract

Cell culture medium (CCM) composition affects cell growth and critical quality attributes (CQAs) of monoclonal antibodies (mAbs) and recombinant proteins. One essential compound needed within the medium is iron because of its central role in many cellular processes. However, iron is also participating in Fenton chemistry leading to the formation of reactive oxygen species (ROS) causing cellular damage. Therefore, this study sought to investigate the impact of iron in CCM on Chinese hamster ovary (CHO) cell line performance, and CQAs of different recombinant proteins. Addition of either ferric ammonium citrate (FAC) or ferric citrate (FC) into CCM revealed major differences within cell line performance and glycosylation pattern, whereby ammonium was not involved in the observed differences. Inductively coupled plasma mass spectrometry (ICP-MS) analysis identified varying levels of impurities present within these iron sources, and manganese impurity rather than iron was proven to be the root cause for increased cell growth, titer, and prolonged viability, as well as altered glycosylation levels. Contrary effects on cell performance and protein glycosylation were observed for manganese and iron. The use of low impurity iron raw material is therefore crucial to control the effect of iron and manganese independently and to support and guarantee consistent and reproducible cell culture processes.

摘要

细胞培养基 (CCM) 的组成会影响单克隆抗体 (mAb) 和重组蛋白的细胞生长和关键质量属性 (CQA)。由于铁在许多细胞过程中起着核心作用，因此培养基中需要一种必需的化合物，即铁。然而，铁也参与 Fenton 化学，导致活性氧 (ROS) 的形成，从而对细胞造成损害。因此，本研究旨在探讨 CCM 中的铁对中国仓鼠卵巢 (CHO) 细胞系性能和不同重组蛋白的 CQA 的影响。在 CCM 中添加柠檬酸铁铵 (FAC) 或柠檬酸铁 (FC) 会导致细胞系性能和糖基化模式出现重大差异，而铵并未参与观察到的差异。电感耦合等离子体质谱 (ICP-MS) 分析确定了这些铁源中存在的杂质水平不同，而锰杂质而不是铁被证明是导致细胞生长、滴度和延长活力增加以及糖基化水平改变的根本原因。锰和铁对细胞性能和蛋白质糖基化的影响相反。因此，使用低杂质的铁原料对于独立控制铁和锰的影响以及支持和保证一致和可重复的细胞培养过程至关重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b96/8459231/49d70b06e45a/BTPR-37-e3148-g001.jpg
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