Development and Analysis of a Mathematical Model for Antibody-Producing GS-NS0 Cells Under Normal and Hyperosmotic Culture Conditions

Abstract

The GS-NS0 cell line is industrially important and is currently used for the large-scale production of several therapeutic monoclonal antibodies. A novel hybrid model, consisting of both unstructured and structured elements, has been developed to describe cell growth and death, metabolism, and antibody production in the GS-NS0 system under normal culture conditions. A comparison between the hybrid model and a large-scale single-cell model (SCM) describing detailed metabolic processes verified the predictive ability of the hybrid model (when compared with experimental data) and highlighted the practical difficulties involved in utilizing complex models. Global sensitivity analysis (GSA) on the hybrid model identified the specific transcription and translation rates of heavy and light immunoglobulin chains as parameters with the largest impact on the antibody production process. This information, together with the addition of a 24-h lag phase, resulted in the successful extension of the hybrid model to represent GS-NS0 system behavior under hyperosmotic culture conditions.

Experimental and In Silico Modelling Analyses of the Gene Expression Pathway for Recombinant Antibody and By-Product Production in NS0 Cell Lines

“…The combination of constant growth rate and constant productivity at the sampling point suggests that the cells are internally in a steady state (File S1). This is consistent with many published modelling studies relying on the same assumption [4], [10], [11], [12], [38], [43].…”

“…1B indicate the relative abundance of the species observed at the sampling time point. Additional monitoring of the change in abundance of the different supernatant species over time allowed us to assign secretion rates for each of these, and to compare secretory activity in our cell lines to previously published data ([4], [38], [43], Fig. 2).…”

“…Secretion rates observed in the cell lines used in this study are compared to a number of published rates for various eukaryotic expression systems [4], [38], [43]. L (light chain), LL (light chain dimer), mAb (assembled monoclonal antibody).…”

“…Modelling approaches have been used in the past for the characterisation of antibody assembly pathways [4], [38], [43]. These studies made predictions with respect to the most likely assembly routes and points of control within the system.…”

“…Such approaches can consider the whole gene expression pathway and the contribution of the different cellular processes to it, allowing both the identification of cellular bottlenecks, and the prediction of how engineering strategies or manipulation of specific steps might impact upon qmAb. A small number of such studies have now shown the proof of concept of such an approach [4], [38], [39]. Indeed, we have previously used a luciferase model system to show that the quantitative determination of gene expression intermediates can be a powerful tool for analysing cell-line specific limitations in gene expression pathways [40].…”