Media supplementation for targeted manipulation of monoclonal antibody galactosylation and fucosylation

岩藻糖基化 糖基化 尿苷二磷酸 中国仓鼠卵巢细胞 岩藻糖 尿苷 岩藻糖基转移酶 单克隆抗体 抗体 生物化学 细胞生长 生物 半乳糖 分子生物学 化学 免疫学 基因 核糖核酸 受体
作者
Evan A. Wells,Liqing Song,Madison Greer,Yu Luo,Varghese Kurian,Babatunde A. Ogunnaike,Anne S. Robinson
出处
期刊:Biotechnology and Bioengineering [Wiley]
卷期号:117 (11): 3310-3321 被引量:10
标识
DOI:10.1002/bit.27496
摘要

Monoclonal antibodies are critically important biologics as the largest class of molecules used to treat cancers, rheumatoid arthritis, and other chronic diseases. Antibody glycosylation is a critical quality attribute that has ramifications for patient safety and physiological efficacy-one that can be modified by such factors as media formulation and process conditions during production. Using a design-of-experiments approach, we examined the effect of 2-F-peracetyl fucose (2FP), uridine, and galactose on cell growth and metabolism, titer, and gene expression of key glycosylation-related proteins, and report how the glycoform distribution changed from Days 4 to 7 in a batch process used for IgG1 production from Chinese hamster ovary cells. We observed major glycosylation changes upon supplement addition, where the addition of 2FP decreased antibody fucosylation by up to 48%, galactose addition increased galactosylation by up to 21%, and uridine addition decreased fucosylation and increased galactosylation by 6% and 2%, respectively. Despite having major effects on glycosylation, neither galactose nor 2FP significantly affected cell culture growth, metabolism, or titer. Uridine improved peak cell densities by 23% but also reduced titer by ∼30%. The supplements caused significant changes in gene expression by Day 4 of the cultures where 2FP addition significantly reduced fucosyltransferase 8 and nucleotide sugar transporter gene expression (by ∼2-fold), and uridine addition significantly increased expression of UDP-GlcNAcT (SLC35A3) and B4GALT1-6 genes (by 1.5-3-fold). These gene expression data alongside glycosylation, metabolic, and growth data improve our understanding of the cellular mechanisms affected by media supplementation and suggest approaches for modifying antibody glycosylation in antibody production processes.
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