Improving lactate metabolism in an intensified CHO culture process: productivity and product quality considerations

Abu-Absi S, Xu S, Graham H, Dalal N, Boyer M, Dave K (2014) Cell culture process operations for recombinant protein production. Adv Biochem Eng Biotechnol 139:35–68 Luan YT, Mutharasan R, Magee WE (1987) Strategies to extend longevity of hybridomas in culture and promote yield of monoclonal antibodies. Biotechnol Lett 9:691–696 Bibila TA, Robinson DK (1995) In pursuit of the optimal fed-batch process for monoclonal antibody production. Biotechnol Prog 11:1–13 Merten OW, Cruz PE, Rochette C, Geny-Fiamma C, Bouquet C, Gonçalves D, Danos O, Carrondo MJT (2001) Comparison of different bioreactor systems for the production of high titer retroviral vectors. Biotechnol Prog 17:326–335 Huang Y-M, Hu W, Rustandi E, Chang K, Yusuf-Makagiansar H, Ryll T (2010) Maximizing productivity of CHO cell-based fed-batch culture using chemically defined media conditions and typical manufacturing equipment. Biotechnol Prog 26:1400–1410 Lu F, Toh PC, Burnett I, Li F, Hudson T, Amanullah A, Li J (2013) Automated dynamic fed-batch process and media optimization for high productivity cell culture process development. Biotechnol Bioeng 110:191–205 Ma N, Ellet J, Okediadi C, Hermes P, McCormick E, Casnocha S (2009) A single nutrient feed supports both chemically defined NS0 and CHO fed-batch processes: improved productivity and lactate metabolism. Biotechnol Prog 25:1353–1363 Gagnon M, Hiller G, Luan Y-T, Kittredge A, DeFelice J, Drapeau D (2011) High-end pH-controlled delivery of glucose effectively suppresses lactate accumulation in CHO fed-batch cultures. Biotechnol Bioeng 108:1328–1337 Konstantinov K, Goudar C, Ng M, Meneses R, Thrift J, Chuppa S, Matanguihan C, Michaels J, Naveh D (2006) The “push-to-low” approach for optimization of high-density perfusion cultures of animal cells. Adv Biochem Eng Biotechnol 101:75–98 Warikoo V, Godawat R, Brower K, Jain S, Cummings D, Simons E, Johnson T, Walther J, Yu M, Wright B, McLarty J, Karey KP, Hwang C, Zhou W, Riske F, Konstantinov K (2012) Integrated continuous production of recombinant therapeutic proteins. Biotechnol Bioeng 109:3018–3029 Clincke M-F, Mölleryd C, Zhang Y, Lindskog E, Walsh K, Chotteau V (2013) Very high density of CHO cells in perfusion by ATF or TFF in WAVE bioreactor™. Part I. Effect of the cell density on the process. Biotechnol Prog 29:754–767 Lim J, Sinclair A, Shevitz J, Bonham-Carter J (2011) An economic comparison of three cell culture techniques. Biopharm Int 24:54–60 Zijlstra G (2013) New approaches in continuous biomanufacturing: continuous XD® cell cultures (at 100 million cells/mL and beyond) coupled to the Rhobust® EBA integrated clarification and purification technology. Integrated continuous biomanufacturing. Castelldefels, Spain Yang WC, Minkler DF, Kshirsagar R, Ryll T, Huang Y-M (2016) Concentrated fed-batch cell culture increases manufacturing capacity without additional volumetric capacity. J Biotechnol 217:1–11 Han YK, Kim Y-G, Kim JY, Lee GM (2010) Hyperosmotic stress induces autophagy and apoptosis in recombinant Chinese hamster ovary cell culture. Biotechnol Bioeng 105:1187–1192 Zhu MM, Goyal A, Rank DL, Gupta SK, Boom TV, Lee SS (2005) Effects of elevated pCO2 and osmolality on growth of CHO cells and production of antibody-fusion protein B1: a case study. Biotechnol Prog 21:70–77 Osman JJ, Birch J, Varley J (2002) The response of GS-NS0 myeloma cells to single and multiple pH perturbations. Biotechnol Bioeng 79:398–407 Langheinrich C, Nienow AW (1999) Control of pH in large-scale, free suspension animal cell bioreactors: alkali addition and pH excursions. Biotechnol Bioeng 66:171–179 Xu S, Abu-Absi S, Pla I, Maranga L (2014) Scale dependence of lactate metabolism in mammalian cell cultures. ACS Spring Meeting, Dallas, TX Qian Y, Khattak SF, Xing Z, He A, Kayne PS, Qian N-X, Pan S-H, Li ZJ (2011) Cell culture and gene transcription effects of copper sulfate on Chinese hamster ovary cells. Biotechnol Prog 27:1190–1194 Luo J, Vijayasankaran N, Autsen J, Santuray R, Hudson T, Amanullah A, Li F (2012) Comparative metabolite analysis to understand lactate metabolism shift in Chinese hamster ovary cell culture process. Biotechnol Bioeng 109:146–156 Kang S, Xiao G, Ren D, Zhang Z, Le N, Trentalange M, Gupta S, Lin H, Bondarenko PV (2014) Proteomics analysis of altered cellular metabolism induced by insufficient copper level. J Biotechnol 189:15–26 Yuk IH, Russell S, Tang Y, Hsu W-T, Mauger JB, Aulakh RPS, Luo J, Gawlitzek M, Joly JC (2015) Effects of copper on CHO cells: cellular requirements and product quality considerations. Biotechnol Prog 31:226–238 Ishida S, Andreux P, Poitry-Yamate C, Auwerx J, Hanahan D (2013) Bioavailable copper modulates oxidative phosphorylation and growth of tumors. Proc Natl Acad Sci USA 110:19507–19512 Zagari F, Jordan M, Stettler M, Broly H, Wurm FM (2013) Lactate metabolism shift in CHO cell culture: the role of mitochondrial oxidative activity. N Biotechnol 30:238–245 Mulukutla BC, Yongky A, Grimm S, Daoutidis P, Hu W-S (2015) Multiplicity of steady states in glycolysis and shift of metabolic state in cultured mammalian cells. PLoS One 10:e0121561 Altamirano C, Paredes C, Cairó JJ, Gòdia F (2000) Improvement of CHO cell culture medium formulation: simultaneous substitution of glucose and glutamine. Biotechnol Prog 16:69–75 Glacken MW, Fleischaker RJ, Sinskey AJ (1986) Reduction of waste product excretion via nutrient control: possible strategies for maximizing product and cell yields on serum in cultures of mammalian cells. Biotechnol Bioeng 28:1376–1389 Wlaschin KF, Hu W-S (2007) Engineering cell metabolism for high-density cell culture via manipulation of sugar transport. J Biotechnol 131:168–176 Berrios J, Altamirano C, Osses N, Gonzalez R (2011) Continuous CHO cell cultures with improved recombinant protein productivity by using mannose as carbon source: metabolic analysis and scale-up simulation. Chem Eng Sci 66:2431–2439 Plagemann PG, Wohlhueter RM, Graff J, Erbe J, Wilkie P (1981) Broad specificity hexose transport system with differential mobility of loaded and empty carrier, but directional symmetry, is common property of mammalian cell lines. J Biol Chem 256:2835–2842 Barngrover D, Thomas J, Thilly WG (1985) High density mammalian cell growth in Leibovitz bicarbonate-free medium: effects of fructose and galactose on culture biochemistry. J Cell Sci 78:173–189 Grainger RK, James DC (2013) CHO cell line specific prediction and control of recombinant monoclonal antibody N-glycosylation. Biotechnol Bioeng 110:2970–2983 Gramer MJ, Eckblad JJ, Donahue R, Brown J, Shultz C, Vickerman K, Priem P, van den Bremer ETJ, Gerritsen J, van Berkel PHC (2011) Modulation of antibody galactosylation through feeding of uridine, manganese chloride, and galactose. Biotechnol Bioeng 108:1591–1602 Hossler P, Wang M, McDermott S, Racicot C, Chemfe K, Zhang Y, Chumsae C, Manuilov A (2015) Cell culture media supplementation of bioflavonoids for the targeted reduction of acidic species charge variants on recombinant therapeutic proteins. Biotechnol Prog 31:1039–1052 Kishishita S, Nishikawa T, Shinoda Y, Nagashima H, Okamoto H, Takuma S, Aoyagi H (2015) Effect of temperature shift on levels of acidic charge variants in IgG monoclonal antibodies in Chinese hamster ovary cell culture. J Biosci Bioeng 119:700–705 Barnabé N, Butler M (1994) Effect of temperature on nucleotide pools and monoclonal antibody production in a mouse hybridoma. Biotechnol Bioeng 44:1235–1245 Sureshkumar GK, Mutharasan R (1991) The influence of temperature on a mouse–mouse hybridoma growth and monoclonal antibody production. Biotechnol Bioeng 37:292–295 Europa AF, Gambhir A, Fu P-C, Hu W-S (2000) Multiple steady states with distinct cellular metabolism in continuous culture of mammalian cells. Biotechnol Bioeng 67:25–34 Maranga L, Goochee CF (2006) Metabolism of PER.C6™ cells cultivated under fed-batch conditions at low glucose and glutamine levels. Biotechnol Bioeng 94:139–150 Chee Furng Wong D, Tin Kam Wong K, Tang Goh L, Kiat Heng C, Gek Sim Yap M (2005) Impact of dynamic online fed-batch strategies on metabolism, productivity and N-glycosylation quality in CHO cell cultures. Biotechnol Bioeng 89:164–177 Xu S, Gupta B, Hoshan L, Chen H (2015) Rapid early process development enabled by commercial chemically defined media and microbioreactors. Biopharm Int 28:28–33 Yongky A, Lee J, Le T, Mulukutla BC, Daoutidis P, Hu W-S (2015) Mechanism for multiplicity of steady states with distinct cell concentration in continuous culture of mammalian cells. Biotechnol Bioeng 112:1437–1445 Templeton N, Dean J, Reddy P, Young JD (2013) Peak antibody production is associated with increased oxidative metabolism in an industrially relevant fed-batch CHO cell culture. Biotechnol Bioeng 110:2013–2024 Charaniya S, Le H, Rangwala H, Mills K, Johnson K, Karypis G, Hu W-S (2010) Mining manufacturing data for discovery of high productivity process characteristics. J Biotechnol 147:186–197 Lee S-Y, Kwon Y-B, Cho J-M, Park K-H, Chang S-J, Kim D-I (2012) Effect of process change from perfusion to fed-batch on product comparability for biosimilar monoclonal antibody. Process Biochem 47:1411–1418 Meuwly F, Weber U, Ziegler T, Gervais A, Mastrangeli R, Crisci C, Rossi M, Bernard A, von Stockar U, Kadouri A (2006) Conversion of a CHO cell culture process from perfusion to fed-batch technology without altering product quality. J Biotechnol 123:106–116