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. 2016 Aug;68(4):1499-511.
doi: 10.1007/s10616-015-9910-9. Epub 2015 Aug 26.

Verhulst and stochastic models for comparing mechanisms of MAb productivity in six CHO cell lines

Nishikant Shirsat  1 , Mohd Avesh  1 , Niall J English  1 , Brian Glennon  1 , Mohamed Al-Rubeai  2
Affiliations

Verhulst and stochastic models for comparing mechanisms of MAb productivity in six CHO cell lines

Nishikant Shirsat et al. Cytotechnology. 2016 Aug.

Abstract

The present study validates previously published methodologies-stochastic and Verhulst-for modelling the growth and MAb productivity of six CHO cell lines grown in batch cultures. Cytometric and biochemical data were used to model growth and productivity. The stochastic explanatory models were developed to improve our understanding of the underlying mechanisms of growth and productivity, whereas the Verhulst mechanistic models were developed for their predictability. The parameters of the two sets of models were compared for their biological significance. The stochastic models, based on the cytometric data, indicated that the productivity mechanism is cell specific. However, as shown before, the modelling results indicated that G2 + ER indicate high productivity, while G1 + ER indicate low productivity, where G1 and G2 are the cell cycle phases and ER is Endoplasmic Reticulum. In all cell lines, growth proved to be inversely proportional to the cumulative G1 time (CG1T) for the G1 phase, whereas productivity was directly proportional to ER. Verhulst's rule, "the lower the intrinsic growth factor (r), the higher the growth (K)," did not hold for growth across all cell lines but held good for the cell lines with the same growth mechanism-i.e., r is cell specific. However, the Verhulst productivity rule, that productivity is inversely proportional to the intrinsic productivity factor (r x ), held well across all cell lines in spite of differences in their mechanisms for productivity-that is, r x is not cell specific. The productivity profile, as described by Verhulst's logistic model, is very similar to the Michaelis-Menten enzyme kinetic equation, suggesting that productivity is more likely enzymatic in nature. Comparison of the stochastic and Verhulst models indicated that CG1T in the cytometric data has the same significance as r, the intrinsic growth factor in the Verhulst models. The stochastic explanatory and the Verhulst logistic models can explain the differences in the productivity of the six clones.

Keywords: Batch cultures; CHO cell lines; MAb productivity; Stochastic models; Verhulst logistic models.

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Figures

Fig. 1
Fig. 1
Verhulst models for the data of the six CHO cell lines: a Growth and b productivity
Fig. 2
Fig. 2
Comparison of productivity potential K x (max) predicted and actual
See this image and copyright information in PMC

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