Metabolic trends of Chinese hamster ovary cells in biopharmaceutical production under batch and fed‐batch conditions

Abstract

Extensive knowledge of Chinese hamster ovary (CHO) cell metabolism is required to improve process productivity and culture performance in biopharmaceutical manufacturing. However, CHO cells show a dynamic metabolism during culturing in batch and fed-batch bioreactors. CHO cell metabolism is generally described as taking place in three stages: exponential growth phase, stationary phase, and death phase. This review aims to summarize the trends of central metabolism for CHO cells during each stage. Additional insights into how culture conditions are related to phase transitions and force metabolic rewiring are provided. Understanding of CHO cell metabolism lends itself to improving culture qualities by, for example, identifying sources of toxic byproducts and pathways for cellular engineering. In summary, this review describes the changes in CHO cell central metabolism over the course of the culture.

Progress in fed-batch culture for recombinant protein production in CHO cells

“…Amino acids deplete in batch culture, which is detrimental to RTP production (Ghaffari et al 2020 ). Amino acids’ feeding is related with tricarboxylic acid cycle (TCA cycle) (Rish et al 2022 ). The TCA cycle depends on alternative metabolites to complement intermediates (Hong et al 2018 ; Ghorbaniaghdam et al 2014 ).…”

“…Malate and glycine accumulation are from the TCA cycle. Cell proliferation has a negative impact with ammonia concentrations above 5 mM (Yang and Butler 2000 ), and ammonia is derived from the hydrolysis of amino acids (Rish et al 2022 ). Thus, controlling feeding of amino acids may reduce byproducts accumulation (Rish et al 2022 ).…”

“…Cell proliferation has a negative impact with ammonia concentrations above 5 mM (Yang and Butler 2000 ), and ammonia is derived from the hydrolysis of amino acids (Rish et al 2022 ). Thus, controlling feeding of amino acids may reduce byproducts accumulation (Rish et al 2022 ). Although cells can synthesize non-essential amino acids, cell growth, and the expression of recombinant proteins still rely on amino acids in feed medium (Horvat et al 2020 ).…”

“…Concentrated feed medium is added in fed-batch culture to replenish nutrients and prolong the culture time (Ritacco et al 2018 ; Chee Furng Wong et al 2005 ). Feed medium can avoid the nutrients limitation, and it can promote higher production of recombinant proteins (Rish et al 2022 ; Bibila and Robinson 1995 ; Lu et al 2013 ). The culture time of cells in stationary phase after fed-batch treatment is longer than that of batch culture (Sellick et al 2015 ).…”

Effects of various disaccharide adaptations on recombinant IgA1 production in CHO-K1 suspension cells

“…1D). This can be attributed to the Warburg effect, in which cells prefer glucose as a source of ATP during the exponential phase (Rish et al 2022). In addition, the disaccharide-adapted cell lines produced more lactate than the nonadapted line.…”