Mechanisms and kinetics of monoclonal antibody synthesis and secretion in synchronous and asynchronous hybridoma cell cultures

Al‐Rubeai, Mohamed; Emery, A. N.

doi:10.1016/0168-1656(90)90066-k

Cited by 132 publications

(58 citation statements)

References 28 publications

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“…Cells arrested at the end of G1-phase of cell cycle are metabolically more active and bigger in size than non-arrested cells (Carvalhal et al 2003;Bi et al 2004). For these reasons, the G1-phase of the cell cycle is considered the ideal time for increased production of recombinant proteins and G1 arrest has been used to increase the productivity in a number of commercially relevant cell lines such as hybridomas and CHO (Al-Rubeai and Emery 1990;Al-Rubeai et al 1992;Moore et al 1997;Fussenegger et al 1998Fussenegger et al , 2000Kaufman et al 1999Kaufman et al , 2001Ibarra et al 2003;Yoon et al 2003a, b;Fogolin et al 2004;Trummer et al 2006). Some studies have reported the S phase as the optimal production phase (Lloyd et al 2000;Fox et al 2005), an example being the increased production of human interferon-c (IFN-c) upon increasing the percentage of CHO in S phase (Fox et al 2005).…”

Section: The Use Of Cell Cycle Arrest To Increase Recombinant Proteinmentioning

confidence: 99%

“…Protein production is dependent on the phase of the cell-cycle and several genes such as those involved in ribosome biogenesis and protein translation are expressed highly in the G1 phase (Al-Rubeai and Emery 1990;Al-Rubeai et al 1992;Moore et al 1997;Fussenegger et al 1998Fussenegger et al , 2000Kaufman et al 1999Kaufman et al , 2001Carvalhal et al 2003;Ibarra et al 2003;Yoon et al 2003a, b;Fogolin et al 2004;Bi et al 2004;Trummer et al 2006). Cells arrested at the end of G1-phase of cell cycle are metabolically more active and bigger in size than non-arrested cells (Carvalhal et al 2003;Bi et al 2004).…”

Section: The Use Of Cell Cycle Arrest To Increase Recombinant Proteinmentioning

confidence: 99%

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Proliferation control strategies to improve productivity and survival during CHO based production culture

2007

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Chinese Hamster Ovary cells are the primary system for the production of recombinant proteins for therapeutic use. Protein productivity is directly proportional to viable biomass, viability and culture longevity of the producer cells and a number of approaches have been taken to optimise these parameters. Cell cycle arrest, particularly in G1 phase, typically using reduced temperature cultivation and nutritional control have been used to enhance productivity in production cultures by prolonging the production phase, but the mechanism by which these approaches work is still not fully understood. In this article, we analyse the public literature on proliferation control approaches as they apply to production cell lines with particular reference to what is known about the mechanisms behind each approach.

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Section: The Use Of Cell Cycle Arrest To Increase Recombinant Proteinmentioning

confidence: 99%

Section: The Use Of Cell Cycle Arrest To Increase Recombinant Proteinmentioning

confidence: 99%

Proliferation control strategies to improve productivity and survival during CHO based production culture

2007

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“…The key underlying source of heterogeneity is cell cycle segregation [5][6][7], which is at the centre of cellular growth, death, and productivity, all of which vary during the different cell cycle phases. Specifically, the cell cycle phase can influence the mAb productivity, both of which have been reported to be cell cycle-, cell line-and promoter-dependent [8,9]. Therefore, a better understanding and knowledge of the cell cycle timing, transitions, and associated production profiles can aid the development (modelling, control, and optimisation) of these industrially-relevant systems [10].…”

Section: Introductionmentioning

confidence: 99%

A Cyclin Distributed Cell Cycle Model in GS-NS0

Munzer

Kostoglou

Georgiadis

et al. 2014

Computer Aided Chemical Engineering

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Mammalian cell cultures are intrinsically heterogeneous at different scales (molecular to bioreactor). The cell cycle is at the centre of capturing heterogeneity since it plays a critical role in the growth, death, and productivity of mammalian cell cultures. Current cell cycle models use biological variables (mass/volume/age) that are non-mechanistic, and difficult to experimentally determine, to describe cell cycle transition and capture culture heterogeneity. To address this problem, cyclins-key molecules that regulate cell cycle transitionhave been utilized. Herein, a novel integrated experimental-modelling platform is presented whereby experimental quantification of key cell cycle metrics (cell cycle timings, cell cycle fractions, and cyclin expression determined by flow cytometry) is used to develop a cyclin and DNA distributed model for the industrially relevant cell line, GS-NS0. Cyclins/DNA synthesis rates were linked to stimulatory/inhibitory factors in the culture medium, which ultimately affect cell growth. Cell antibody productivity was characterized using cell cyclespecific production rates. The solution method delivered fast computational time that renders the model's use suitable for model-based applications. Model structure was studied by global sensitivity analysis (GSA), which identified parameters with a significant effect on the model output, followed by re-estimation of its significant parameters from a control set of batch experiments. A good model fit to the experimental data, both at the cell cycle and viable cell density levels, was observed. The cell population heterogeneity of disturbed (after cell arrest) and undisturbed cell growth was captured proving the versatility of the modelling approach. Cell cycle models able to capture population heterogeneity facilitate in depth understanding of these complex systems and enable systematic formulation of culture strategies to improve growth and productivity. It is envisaged that this modelling approach will pave the model-based development of industrial cell lines and clinical studies.PLOS Computational Biology |

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“…In spite of the mechanism by which the control of cell cycle regulates the protein secretion is still unclear, some authors think that there is a relationship between the protein production and the phase of the cell cycle, since those genes involved in ribosome synthesis and protein translation are expressed mainly in the G1 phase (Al-Rubeai and Emery 1990;Al-Rubeai et al 1992). Other workers consider the G1 as the ideal phase of the cell cycle to increase the productivity of monoclonal antibodies (mAb) and recombinant proteins with rising biopharmaceutical relevance (Kromenaker and Srienc 1991;Trummer et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Effects of hydroxyurea on monoclonal antibody production induced by anti-mIgG and LPS stimulation on murine B cell hybridomas

et al. 2010

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Chemical treatment with hydroxyurea (HU) has been selected as a simple and low cost strategy to generate a cell population enriched for the G1 phase. After the chemical treatment with HU, cells were stimulated with anti-mIgG to test if the positive effects of anti-mIgG on CD40 expression and specific IgG2a production rate were improved upon a cell population with a higher percentage of cells in G1 phase at the beginning of the cell culture. In addition, other treatments assayed in this work were the cell stimulation with Lipopolysaccharide (LPS) both before and after the HU treatment. It has been observed that the use of HU under conditions able to maintain the cells in viable state (0.1 mM for 20 h), has a negative effect on CD40 expression and specific IgG2a production rate induced by anti-mIgG. The positive effect of LPS on cell stimulation induced by anti-mIgG is reduced on cells treated with HU.

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Mechanisms and kinetics of monoclonal antibody synthesis and secretion in synchronous and asynchronous hybridoma cell cultures

Cited by 132 publications

References 28 publications

Proliferation control strategies to improve productivity and survival during CHO based production culture

Proliferation control strategies to improve productivity and survival during CHO based production culture

A Cyclin Distributed Cell Cycle Model in GS-NS0

Effects of hydroxyurea on monoclonal antibody production induced by anti-mIgG and LPS stimulation on murine B cell hybridomas

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