A semi-empirical glycosylation model of a camelid monoclonal antibody under hypothermia cell culture conditions

Aghamohseni, Hengameh; Spearman, Maureen; Ohadi, Kaveh; Braasch, Katrin; Moo‐Young, Murray; Butler, Michael; Budman, Hector

doi:10.1007/s10295-017-1926-z

Cited by 12 publications

(13 citation statements)

References 38 publications

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“…The temperature shift led to an overall increase, amounting to 2.3–5.6% of HM. Mild hypothermia has been shown to impact galactosylation depending on media composition, cell line, and protein type (Abu‐Absi et al, ; Aghamohseni, ; Sou et al, ). As expected based upon biological knowledge, the media supplements weakly influenced the abundance of afucosylated species.…”

Section: Resultsmentioning

confidence: 99%

Parallel experimental design and multivariate analysis provides efficient screening of cell culture media supplements to improve biosimilar product quality

Brühlmann¹,

Sokolov

Butté

et al. 2017

Biotech & Bioengineering

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Rational and high-throughput optimization of mammalian cell culture media has a great potential to modulate recombinant protein product quality. We present a process design method based on parallel design-of-experiment (DoE) of CHO fed-batch cultures in 96-deepwell plates to modulate monoclonal antibody (mAb) glycosylation using medium supplements. To reduce the risk of losing valuable information in an intricate joint screening, 17 compounds were separated into five different groups, considering their mode of biological action. The concentration ranges of the medium supplements were defined according to information encountered in the literature and in-house experience. The screening experiments produced wide glycosylation pattern ranges. Multivariate analysis including principal component analysis and decision trees was used to select the best performing glycosylation modulators. Subsequent D-optimal quadratic design with four factors (three promising compounds and temperature shift) in shake tubes confirmed the outcome of the selection process and provided a solid basis for sequential process development at a larger scale. The glycosylation profile with respect to the specifications for biosimilarity was greatly improved in shake tube experiments: 75% of the conditions were equally close or closer to the specifications for biosimilarity than the best 25% in 96-deepwell plates. Biotechnol. Bioeng. 2017;114: 1448-1458. © 2017 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Parallel experimental design and multivariate analysis provides efficient screening of cell culture media supplements to improve biosimilar product quality

Brühlmann¹,

Sokolov

Butté

et al. 2017

Biotech & Bioengineering

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“…It also provides the mean squared error for the prediction [27]. Equation (7) shows the general equation of the kriging model required to predict (x ).…”

Section: Kriging and Dynamic Kriging Model Buildingmentioning

confidence: 99%

“…A similar trend was observed in the studies from Refs. [7,32]. The pH value's effect on viable cell and glucose concentration is not considered in this work.…”

Section: Prediction Of Temperature and Ph Effect Using The Kinetic Modelmentioning

confidence: 99%

“…In a previous study, it was shown that the protein specific production rate and glycan fractions are affected by different temperatures in the CHO cell culture. In general, for mAbs, the shifting of temperature usually causes an increase in protein production rate, while decreasing the temperature usually causes a reduction in glycosylation processes, such that the galactosylation, fucosylation and sialyation are reduced [7,22].…”

Section: Prediction Of Temperature and Ph Effect Using The Kinetic Modelmentioning

confidence: 99%

“…The major glycosylation reactions, where sugar covalently binds to the polypeptide backbone of a protein, happen in the lumina of the cis-, medial-or trans-Golgi cisternae [5]. In the bioreactor culture system, the glycosylation process can be affected by both chemical and physical stimuli for the same cell line [3,7,8]. These stimuli can change the cell metabolism, such as the glycolytic pathway, purine/pyrimidine metabolism or the TCA cycle, which influence the synthesis and function of nucleotide donors, glycosyltransferases and glycosidase, and further affect the biocatalytic reactions of glycosylation [9].…”

Section: Introductionmentioning

confidence: 99%

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mAb Production Modeling and Design Space Evaluation Including Glycosylation Process

Ierapetritou

2021

Processes

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Due to high demand, monoclonal antibodies (mAbs) production needs to be efficient, as well as maintaining a high product quality. Quality by design (QbD) via predictive process modeling greatly facilitates process understanding and can be used to adjust process parameters to further improve the unit operations. In this work, mechanistic and dynamic kriging models are developed to capture the protein productivity and glycan fractions under different temperatures and pH levels. The design of experiments is used to generate input and output data for model training. The dynamic kriging model shows good performance in capturing the dynamic profiles of cell cultures and glycosylation using only limited input data. The developed model is further used for feasibility analysis, and successfully identifies the operating design space, maintaining high productivity and guaranteed product quality.

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Continuous optical in‐line glucose monitoring and control in CHO cultures contributes to enhanced metabolic efficiency while maintaining darbepoetin alfa product quality

Lederle

Tric

Roth

et al. 2021

Biotechnology Journal

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Great efforts are directed towards improving productivity, consistency and quality of biopharmaceutical processes and products. One particular area is the development of new sensors for continuous monitoring of critical bioprocess parameters by using online or in‐line monitoring systems. Recently, we developed a glucose biosensor applicable in single‐use, in‐line and long‐term glucose monitoring in mammalian cell bioreactors. Now, we integrated this sensor in an automated glucose monitoring and feeding system capable of maintaining stable glucose levels, even at very low concentrations. We compared this fed‐batch feedback system at both low (< 1 mM) and high (40 mM) glucose levels with traditional batch culture methods, focusing on glycosylation and glycation of the recombinant protein darbepoetin alfa (DPO) produced by a CHO cell line. We evaluated cell growth, metabolite and product concentration under different glucose feeding strategies and show that continuous feeding, even at low glucose levels, has no harmful effects on DPO quantity and quality. We conclude that our system is capable of tight glucose level control throughout extended bioprocesses and has the potential to improve performance where constant maintenance of glucose levels is critical.

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A semi-empirical glycosylation model of a camelid monoclonal antibody under hypothermia cell culture conditions

Cited by 12 publications

References 38 publications

Parallel experimental design and multivariate analysis provides efficient screening of cell culture media supplements to improve biosimilar product quality

Parallel experimental design and multivariate analysis provides efficient screening of cell culture media supplements to improve biosimilar product quality

mAb Production Modeling and Design Space Evaluation Including Glycosylation Process

Continuous optical in‐line glucose monitoring and control in CHO cultures contributes to enhanced metabolic efficiency while maintaining darbepoetin alfa product quality

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