Chapter 12 : Mammalian Cell Culture for Biopharmaceutical Production

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $30.00

Preview this chapter:
Zoom in

Mammalian Cell Culture for Biopharmaceutical Production, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816827/9781555815127_Chap12-1.gif /docserver/preview/fulltext/10.1128/9781555816827/9781555815127_Chap12-2.gif


This chapter summarizes the recent developments of biopharmaceutical production using mammalian cell culture, and focuses on monoclonal antibodies (MAbs), which is the most dominant and most rapidly developing sector in the biopharmaceutical industry, and its large-scale production the most established. Two expression vector systems dominate antibody production in mammalian cell culture, one based on dihydrofolate reductase (DHFR) genes and the other on glutamine synthetase (GS) genes. To improve outgrowth and transfection efficiency, transfection is predominantly performed in serum-containing media, but using host or parental cell lines preadapted to grow in suspension and serum-free media reduces adaptation times and increases the likelihood of reaching high cell densities and high product yields in serum-free suspension culture. Apoptosis is induced by various chronic insults and is mediated by several mechanisms. Various strategies were implemented to inhibit apoptosis, including the prevention of nutrient limitation by fed-batch operation, which can delay the onset and extent of apoptosis, and engineering of resistance into the cell line, such as the regulatory Bcl-2 family of proteins, which affect the activation of apoptosis pathways in cells. Novel technologies such as enhanced expression systems, automated screening methods, cell line engineering, improved process monitoring, and disposable apparatuses are leading to more productive and efficient production of biopharmaceuticals by mammalian cell culture.

Citation: Zhang J. 2010. Mammalian Cell Culture for Biopharmaceutical Production, p 157-178. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch12

Key Concept Ranking

Tumor Necrosis Factor alpha
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


1. Allison, D. W.,, K. A. Aboytes,, D. K. Fong,, S. L. Leugers,, T. K. Johnson, and, H. N. Loke. 2005. Development and optimization of cell culture media: genomic and proteomic approaches. BioProcess Int. 3:38 2001.
2. Al-Rubeai, M., and, R. P. Singh. 1998. Apoptosis in cell culture. Curr. Opin. Biotechnol. 9:152156.
3. Altamirano, C.,, C. Paredes,, A. Illanes,, J. J. Cairo, and, F. Godia. 2004. Strategies for fed-batch cultivation of t-PA producing CHO cells: substitution of glucose and gluta-mine and rational design of culture medium. J. Biotechnol. 110:171179.
4. Anderson, D. C., and , L. Krummen. 2002. Recombinant protein expression for therapeutic applications. Curr. Opin. Biotechnol. 13:117123.
5. Anderson, D. C., and , D. E. Reilly. 2004. Production technologies for MAbs and their fragments. Curr. Opin. Biotechnol. 15:456462.
6. Arden, N., and , M. J. Betehbaugh. 2004. Life and death in mammalian cell culture: strategies for apoptosis inhibition. Trends Biotechnol. 22:174180.
7. Baer, A., and , J. Bode. 2001. Coping with kinetics and thermodynamic barriers: RMCE, an effective strategy for the targeted integration of transgenes. Curr. Opin. Biotechnol. 12:473480.
8. Baez, J.,, D. Olson, and, J. W. Polarek. 2005. Recombinant microbial systems for the production of human collagen and gelatin. Appl. Microbiol. Biotechnol. 69:245252.
9. Bailey, C. G.,, A. S. Tait, and, N. A. Sunstrom. 2002. High-throughput clonal selection of recombinant CHO cells using a dominant selectable and amplifiable metallothionein-GFP fusion protein. Biotechnol. Bioeng. 80:670676.
10. Baker, K. N.,, M. H. Rendall,, A. E. Hills,, M. Hoare,, R. B. Freedman, and, D. C. James. 2001. Metabolic control of recombinant protein N-glycan processing in NS0 and CHO cells. Biotechnol. Bioeng. 73:188202.
11. Baldi, L.,, N. Muller,, S. Picasso,, R. Jacquet,, P. Girard,, H. P. Thanh,, E. Derow, and, F. M. Wurm. 2005. Transient gene expression in suspension HEK-293 cells: application to large-scale protein production. Biotechnol. Prog. 21:148153.
12. Barnes, L. M.,, C. M. Bentley, and, A. J. Dickson. 2000. Advances in animal cell recombinant protein production: GS-NS0 expression system. Cytotechnology 32:109123.
13. Barnes, L. M.,, C. M. Bentley, and, A. J. Dickson. 2001. Characterization of the stability of recombinant protein production in GS-NS0 expression system. Biotechnol. Bioeng. 73:261270.
14. Barnes, L. M.,, C. M. Bentley, and, A. J. Dickson. 2003. Stability of protein production from recombinant mammalian cells. Biotechnol. Bioeng. 81:631639.
15. Barnes, L. M.,, C. M. Bentley,, N. Moy, and, A. J. Dickson. 2007. Molecular analysis of successful cell line selection in transfected GS-NS0 myeloma cells. Biotechnol. Bioeng. 96:337348.
16. Bebbington, C. R.,, G. L. Renner,, S. Thomson,, D. King,, D. Abrams, and, G. T. Yarranton. 1992. High level expression of a recombinant antibody from myeloma cells using a glutamine synthetase gene as an amplifiable selectable marker. Bio/Technology 10:169175.
17. Beck, A.,, E. Wagner-Rousset,, M. C. Bussat,, M. Lokteff,, C. Klinguer-Hamour,, J. F. Haeuw,, L. Goetsch,, T. Wurch,, A. van Dorsselaer, and, N. Corvaia. 2008. Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr. Pharm. Biotechnol. 9:482501.
18. Beck, A.,, T. Wurch, and, N. Corvaia. 2008. Therapeutic antibodies and derivatives: from the bench to the clinic. Curr. Pharm. Biotechnol. 9:421422.
19. Benton, T.,, T. Chen,, M. McEntee,, B. Fox,, D. King,, R. Crombie, and, T. C. Thomas. 2002. The use of UCOE vectors in combination with a preadapted serum free, suspension cell line allows for rapid production of large quantities of protein. Cytotechnology 38:4346.
20. Bi, J. X.,, J. Shuttleworth, and , M. Al-Rubeai. 2001. Uncoupling of cell growth and proliferation results in enhancement of productivity in p21CIP1-arrested CHO cells. Biotechnol. Bioeng. 85:741749.
21. Birch, J. R. 2000. Cell products—antibodies, p. 411–424. In R. E. Spier (ed.), Encyclopedia of Cell Technology. John Wiley & Sons, Inc., Hoboken, NJ.
22. Birch, J. R.,, J. Bonnerjea, and , S. Flatman. 1995. The production of monoclonal antibodies, p. 231–265. In J. R. Birch and, E. S. Lennox (ed.), Monoclonal Antibodies: Principles and Applications. John Wiley & Sons, Inc., Hoboken, NJ.
23. Birch, J. R.,, D. O. Mainwaring, and, A. J. Racher. 2005. Use of the glutamine synthetase (GS) expression system for the rapid development of highly productive mammalian cell processes, p. 809–832. In J. Knablein (ed.), Modern Biopharmaceuticals. Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim, Germany.
24. Birch, J. R., and , A. J. Racher. 2006. Antibody production. Adv. Drug Delivery Rev. 58:671685.
25. Bohm, E.,, R. Voglauer,, W. Steinfellner,, R. Kunert,, N. Borth, and, H. Katinger. 2004. Screening for improved cell performance: selection of subclones with altered production kinetics of improved stability by cell sorting. Biotechnol. Bioeng. 88:699706.
26. Borth, N.,, D. Mattanovich,, R. Kunert, and, H. Katinger. 2005. Effect of increased expression of protein disulfide isomerase and heavy chain binding protein on antibody secretion in a recombinant CHO cell line. Biotechnol. Prog. 21:106111.
27. Bowering, L. C. 2004. Microbial systems for the manufacture of therapeutic antibody fragments. BioProcess Int. 2:4047.
28. BPI Reports. 2001. MAb market predicted to continue dominating. BioProcess Int. 5:8.
29. Broedel, S., Jr., and, S. M. Papciak. 2003. The case for serum-free media. BioProcess Int. 1:5658.
30. Brower, A. 2005. Number of monoclonal antibodies on market nearly doubles by 2008. Biotechnol. Healthcare June:64.
31. Browne, S. M., and , M. Al-Rubeai. 2007. Selection methods for high-producing mammalian cell lines. Trends Biotechnol. 25:425432.
32. Burgener, A., and , M. Butler. 2006. Medium development, p. 41–80. In S. S. Ozturk and, W.-S. Hu (ed.), Cell Culture Technology for Pharmaceutical and Cell-Based Therapies (Biotechnology and Bioprocessing Series). CRC Press, Boca Raton, FL.
33. Burky, J. E.,, M. C. Wesson,, A. Young,, S. Farnsworth,, B. Dionne, and, Y. Zhu. 2007. Protein-free fed-batch culture of non-GS NS0 cell lines for production of recom-binant antibodies. Biotechnol. Bioeng. 96:281293.
34. Burteau, C. C.,, F. R. Verhoeye,, J. F. Mols,, J. S. Ballez,, S. N. Agathos, and, Y. J. Schneider. 2003. Fortification of a protein-free cell culture medium with plant peptones improves cultivation and productivity of an interferon-g-producing CHO cell line. In Vitro Cell. Dev. Biol. Anim. 39:291296.
35. Butler, M. 2005. Animal cell cultures: recent achievements and perspectives in the production of biopharmaceuticals. Appl. Microbiol. Biotechnol. 68:283291.
36. Carvell, J. P. 2008. Viable biomass sensor for bioreactors. BIO Forum Europe 9:5455.
37. Center for Drug Evaluation and Research. 2001. Guideline on General Principles of Process Validation. U.S. Food and Drug Administration, Rockville, MD.
38. Chattopadhyay, S., and , L. Pavithra. 2007. MARs and MARBPs: key modulators of gene regulation and disease manifestation. Subcell. Biochem. 41:213230.
39. Chen, P., and , S. W. Harcum. 2007. Identification of genes sensitive to ammonium in CHO cell cultures using a differential display. Appl. Biochem. Biotechnol. 141:349360.
40. Chu, L., and , D. Robinson. 2001. Industrial choices for protein production by large-scale cell culture. Curr. Opin. Biotechnol. 12:180187.
41. Chun, B. H.,, J. H. Kim,, H. J. Lee, and, N. Chung. 2007. Usability of size-excluded fractions of soy protein hydrolysates for growth and viability of Chinese hamster ovary cells in protein-free suspension culture. Bioresour. Technol. 98:10001005.
42. Clark, R. G.,, D. Mortensen,, D. Reifsynder,, M. Mohler,, T. Etcheverry, and, V. Mukku. 1993. Recombinant human insulin-like growth factor binding protein-3 (rhIGFBP-3): effects on the glycemic and growth promoting activities of rhIGF-1 in the rat. Growth Regul. 3:5052.
43. Coco-Martin, J. M. 2004. Mammalian expression of therapeutic proteins—a review of advancing technology. BioProcess Int. 2:3240.
44. Coco-Martin, J. M., and, M. M. Harmsen. 2008. A review of therapeutic protein expression by mammalian cells. BioProcess Int. 6:S28S33.
45. Coloma, M. J.,, A. Clift,, L. Wims, and, S. L. Morrison. 2000. The role of carbohydrate in the assembly and function of polymeric IgG. Mol. Immunol. 37:10811090.
46. Cui, L. 2004. Microbial process development for biopharmaceuticals. BioProcess Int. 2:3239.
47. Davies, C. G.,, M. L. Gallo, and, J. R. F. Corvalan. 1999. Transgenic mice as a source of fully human antibodies for the treatment of cancer. Cancer Metastasis Rev. 18:421425.
48. Deeds, Z. W.,, S. Updike,, B. J. Cutak, and, M. V. Caple. 2007. Working towards a chemically-defined replacement for hydrolysates, p. 649–651. In R. Smith (ed.), Cell Technology for Cell Products. Proceedings of the 19th ESACT Meeting, Harrogate, UK. Springer, Dordrecht, The Netherlands.
49. Deer, J. R., and , D. S. Allison. 2004. High-level expression proteins in mammalian cells using transcription regulatory sequences from the Chinese hamster EF1-a gene. Biotechnol. Prog. 20:880889.
50. De Jesus, M. J., and, F. M. Wurm. 2009. Medium and process optimization for high yield, high density suspension cultures: from low throughput spinner flasks to high throughput milliliter reactors. BioProcess Int. 7:S12S17.
51. DeMaria, C. T.,, V. Cairnes,, C. Schwarz,, J. Zhang,, M. Guerin, and, E. Zuena. 2007. Accelerated clone selection for recombinant CHO cells using a FACS-based high-throughput screen. Biotechnol. Prog. 23:465472.
52. Dempsey, J.,, S. Ruddock,, M. Osborne,, A. Ridley,, S. Sturt, and, R. Field. 2003. Improved fermentation processes for NS0 cell lines expressing human antibodies and glutamine synthetase. Biotechnol. Prog. 19:175178.
53. Deo, Y. M.,, M. D. Mahadevan, and, R. Fuchs. 1996. Practical considerations in operation and scale-up of spin-filter based bioreactors for monoclonal antibody production. Biotechnol. Prog. 12:5764.
54. DePalma, A. 2008. Strengthening mammalian cell culture. Genet. Eng. Biotechnol. News 28(18).
55. Derouazi, M. 2004. Serum-free large-scale transient transfection of CHO cells. Biotechnol. Bioeng. 87:537545.
56. DeZengotita, V. M.,, P. Girard,, F. Van Tilborgh,, K. Iglesias,, N. Muller,, M. Bertschinger, and, F. M. Wurm. 2000. Phosphate feeding improves high-cell-concentration for monoclonal antibody production. Biotechnol. Bioeng. 69:566576.
57. Dinnis, D. M., and , D. C. James. 2005. Engineering mammalian cell factories for improved recombinant monoclonal antibody production: lessons from nature? Biotechnol. Bioeng. 91:180189.
58. Douglas, A. S. 2005. Efficient product development—a systems approach. BioProcess Int. 3:2627.
59. Dubel, S. 2007. Recombinant therapeutic antibodies. Appl. Microbiol. Biotechnol. 74:723729.
60. Duncan, A., and , G. Hadlaczky. 2007. Chromosomal engineering. Curr. Opin. Biotechnol. 18:420424.
61. Eibl, R., and , D. Eibl. 2009. Disposable bioreactors in cell culture-based upstream processing. BioProcess Int. 7:S18-S23.
62. European Medicines Evaluation Agency. 2002. Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathies via human and veterinary medicinal products. EMEA/410/01, Rev. 2. EMEA, London, United Kingdom.
63. Farges-Haddani, B.,, B. Tessier,, S. Chenu,, I. Chevalot,, C. Harscoat,, I. Marc,, J. L. Goergen, and, A. Marc. 2006. Peptide fractions of rapeseed hydrolysates as an alternative to animal proteins in CHO cell culture media. Process Biochem. 41:22972304.
64. Field, R. P. July, 2003. Animal cell culture. U.S. patent 6,593,140 (Assignee: Lonza Group AG).
65. Figueroa, B., Jr.,, E. Ailor,, D. Osborne,, J. M. Hardwick,, M. Reff, and, M. J. Betenbaugh. 2007. Enhanced cell culture performance using inducible anti-apoptotic genes E1B-19K and Aven in the production of a monoclonal antibody with Chinese hamster ovary cells. Biotechnol. Bioeng. 97:877892.
66. Fire, A.,, S. Xu,, M. K. Montgomery,, S. A. Kostas,, S. E. Driver, and, C. C. Mello. 1998. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806811.
67. Fisch, I. 2007. The role of matrix-attachment regions in increasing recombinant protein expression. BioProcess Int. 5:6672.
68. Fisher, M. 2006. A stirred-tank bioreactor delivered in eight weeks and one hour. BioProcess Int. 4:S28S30.
69. Fletcher, T. 2005. Designing culture media for recombinant protein production: a rational approach. BioProcess Int. 3:3036.
70. Food and Drug Administration. 2001. Guidance for industry: Q5E comparability of biotechnological/biological products subject to changes in their manufacturing process (ICH). Food and Drug Administration, Rockville, MD. (Online.) http://www.fda.gov/downloads/Drugs/GuidanceCompliance-RegulatoryInformation/Guidances/ucm073476.pdf.
71. Food and Drug Administration. 2001. Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs; general (21 CFR, Part 210) Food and Drug Administration, Rockville, MD. (Online.) http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/ CFRSearch.cfm?CFRPart=210&showFR=1.
72. Food and Drug Administration. 2001. Current good manufacturing practices for finished pharmaceuticals (21 CFR, Part 211). Food and Drug Administration, Rockville, MD. (Online.) http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211&showFR=1.
73. Forno, G.,, M. Bollati fogolin,, M. Oggero,, R. Kratje,, M. Etcheverrigaray,, H. S. Conradt, and, M. Nimtz. 2004. N- and O-linked carbohydrates and glycosylation site occupancy in recombinant human granulocyte-macrophage colony-stimulating factor secreted by a Chinese hamster ovary cell line. Eur. J. Biochem. 271:907919.
74. Fox, S. 2004. Maximizing outsourced biopharma production. Contract Pharma. June:7278..
75. Franek, F. 2004. Gluten of spelt wheat (Triticum aestivum subspecies spelta) as a source of peptides promoting viability and product yield of mouse hybridoma cell cultures. J. Agric. Food Chem. 52:40974100.
76. Franek, F. 2004. Peptide modulates growth and productivity of mammalian cell cultures and suppress apoptosis. BioProcess Int. 2:4852.
77. Franek, F.,, T. Eckschlager,, H. Katinger. 2003. Enhancement of monoclonal antibody production by lysine-containing peptides. Biotechnol. Prog. 19:169174.
78. Fukuda, Y., and , S. Nishikawa. 2003. Matrix attachment regions enhance transcription of a downstream transgene and the accessibility of its promoter region to micrococcal nuclease. Plant Mol. Biol. 51:665675.
79. Fussenegger, M., and , J. E. Bailey. 1998. Molecular regulation of cell-cycle progression and apoptosis in mammalian cells: implications for biotechnology. Biotechnol. Prog. 14:807833.
80. Fux, C.,, S. Moser,, S. Schlatter,, M. Rimann,, J. E. Bailey, and, M. Fussenegger. 2001. Streptogramin- and tetracy-cline-responsive dual regulated expression of p27Kip1 sense and antisense enables positive and negative growth control of Chinese hamster ovary cell. Nucleic Acids Res. 29:E19.
81. Galbraith, D. N. 2002. Transmissible spongiform encephalopathies and tissue cell culture. Cytotechnology 39:117124.
82. Gambhir, A.,, C. Zhang,, A. Europa, and , W.-S. Hu. 2001. Analysis of the use of fortified medium in continuous culture of mammalian cells. Cytotechnology 31:243254.
83. Gasser, B., and , D. Mattanovich. 2007. Antibody production with yeasts and filamentous fungi: on the road to large scale? Biotechnol. Lett. 29:201212.
84. Ge, X.,, M. Hanson,, H. Shen,, Y. Kostov,, K. A. Brorson,, D. D. Fray,, A. Moreira, and , G. Rao. 2006. Validation of an optical sensor-based high-throughput bioreactor system for mammalian cell culture. J. Biotechnol. 122:293306.
85. Gellissen, G.,, A. W. M. Strasser, and, M. Suckow. 2005. Key and criteria to the selection of an expression platform, p. 1–6. In G. Gellissen (ed.), Production of Recombinant Proteins: Novel Microbial and Eucaryotic Expression Systems. Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim, Germany.
86. Gerngross, T. 2004. Advances in the production of human therapeutic protein in yeasts and filamentous fungi. Nat. Biotechnol. 22:14091414.
87. Gerson, D. F., and , B. Mukherjee. 2005. Manufacturing process development for high-volume, low-cost vaccines. BioProcess Int. 3:4250.
88. Gillies, S. D.,, H. Dorai,, J. Wasolowski,, G. Majeau,, D. Young,, J. Boyd,, J. Gardner, and, K. James. 1989. Expression of human anti-tetanus toxoid antibody in transfected murine myeloma cells. Bio/Technology 7:799804.
89. Goochee, C. F. 2002. The role of a process development group in biopharmaceutical process startup. Cytotechnology 38:6376.
90. Gorfien, S.,, R. M. Fike,, J. L. Dzimian,, J. P. Godwin,, P. J. Price,, D. A. Epstein,, D. Gruber, and , C. Mcclure. 2000. Growth of NS0 cells in protein-free, chemically-de fined medium. Biotechnol. Prog. 16:682687.
91. Graumann, K., and , A. Premstaller. 2006. Manufacturing of recombinant therapeutic proteins in microbial systems. Biotechnol. J. 1:164168.
92. Grillari, J.,, K. Fortschegger,, R. M. Grabherr,, O. Hohenwarter,, R. Kunert, and, H. Katinger. 2001. Analysis of alterations in gene expression after amplification of recombinant genes in CHO cells. J. Biotechnol. 87:5965.
93. Grosvenor, S. 2008. The role of media development in process optimization: an historical perspective. In Guide to Protein Production. BioPharm Int. 21:S28S36.
94. Hacker, D. L.,, S. Nallet, and, F. M. Wurm. 2008. Recombinant protein production yields from mammalian cells: past, present, and future. In Guide to Protein Production. BioPharm Int. 21:S6S14.
95. Hamilton, S. R., and , T. U. Gerngross. 2007. Glycosylation engineering in yeasts: the advent of fully humanized yeast. Curr. Opin. Biotechnol. 18:387392.
96. Harms, P.,, Y. Kostov, and, G. Rao. 2002. Bioprocess monitoring. Curr. Opin. Biotechnol. 13:124127.
97. Hellman, K. B.,, J. P. Honstead, and, C. K. Vincent. 1996. Adventitious agents from animal-derived raw materials and production systems. Dev. Biol. Stand. 88:231234.
98. Hewlett, G. 1991. Strategies for optimizing serum-free media. Cytotechnology 5:314.
99. Hills, A. E.,, A. Patel,, P. Boyd, and , D. C. James. 2001. Metabolic control of recombinant monoclonal anti body N-glycosylation in GS-NS0 cells. Biotechnol. Bioeng. 75:239251.
100. Ho, L.,, S. E. Lee, and, A. E. Humphrey. 2003. Industrial cell culture: principles, processes and products, p. 1046–1072. In J. A. Kent (ed.), Reigel’s Handbook of Industrial Chemistry, 10th ed. Springer, Berlin, Germany.
101. Hollis, G. F., and , G. E. Mark. June 2004. Homologous recombination antibody expression system for murine cells. U.S. Patent 6,750,041.
102. Holmes, P., and , M. Al-Rubeai. 1999. Improved cell line development by a high throughput affinity capture surface display technique to select for high secretors. J. Immunol. Methods 230:141147.
103. Huang, E. P.,, C. P. Marquis, and , P. P. Gray. 2004. Process development for a recombinant Chinese hamster ovary (CHO) cell line utilizing a metal-induced and amplified metallothionein expression system. Biotechnol. Bioeng. 88:437450.
104. Humphreys, D. P. 2003. Production of antibodies and antibody fragments in Escherichia coli and a comparison of their functions, uses and modifications. Curr. Opin. Drug Discov. Devel. 6:188196.
105. Ifandi, V., and , M. Al-Rubeai. 2005. Regulation of cells by the coexpression of c-Myc and Bcl-2. Biotechnol. Prog. 21:671677.
106. Inoue, Y.,, L. B. Lopez,, S. Kawamoto,, N. Arita,, K. Teruya,, M. K. Seki,, M. Shoji,, S. Karmei,, Y. Hashizume,, H. Shiozawa,, H. Tachibana,, K. Ohashi,, T. Yasumoto,, T. Suzuki,, K. Imai,, M. Nomoto,, Y. Takenoyama, and , S. Katakura. 1996. Production of recombinant human monoclonal antibody using ras-amplified BHK-21 cells in a protein-free medium. Biosci. Biotechnol. Biochem. 60:811817.
107. Ishaque, A., and , M. Al-Rubeai. 2002. Role of vitamins in determining apoptosis and extent of suppression by bcl-2 during hybridoma cell culture. Apoptosis 7:231239.
108. Jakovcic, K. 2007. Biomanufacturing strategies: market drivers, build-vs-buy decisions and opportunities in contract relationship management. Business Insights Ltd., London, UK. (Online.) www.globalbusinessinsights.com.
109. Jayme, D. W. 1999. An animal origin perspective of common constituents of serum-free medium formulations. Dev. Biol. Stand. 99:181187.
110. Jefferis, R. 2005. Glycosylation of recombinant antibody therapeutics. Biotechnol. Prog. 21:1116.
111. Jenkins, N. 2003. Analysis and manipulation of recombinant glycoproteins manufactured in mammalian cell culture, p. 3–20. In V. A. Vinci and, S. R. Parekh (ed.), Handbook of Industrial Cell Culture: Mammalian, Microbial, and Plant Cells. Humana Press, Totowa, NJ.
112. Jenkins, N.,, R. B. Parekh, and, D. C. James. 1996. Getting the glycosylation right: implications for the biotechnology industry. Nat. Biotechnol. 14:975981.
113. Jones, D.,, N. Kroos,, R. Anema,, B. van Montfoort,, A. Vooys,, S. van der Kraats,, E. van der Helm,, S. Smits,, J. Schouten,, K. Brouwer,, F. Lagerwerf,, P. van Berkel,, D. J. Opstelten,, T. Logtenberg, and, A. Bout. 2003. High-level expression of recombinant IgG in the human cell line PER.C6. Biotechnol. Prog. 19:163168.
114. Jones, S. D.,, F. J. Castillo, and, H. L. Levine. 2007. Advances in the development of therapeutic monoclonal antibodies. BioPharm Int. 20:96114.
115. Julien, C. 2006. Production of humanlike recombinant proteins in Pichia pastoris: from expression vector to fermentation strategy. BioProcess Int. 4:2233.
116. Julien, C. 1998. Scaling-up from spinners, T-flasks and shakers: a versatile bioreactor for mammalian and microbial cells. Am. Biotechnol. Lab. 16(6):1213.
117. Jung, B.,, S. Lee,, I. H. Yang,, T. Good, and, G. L. Cote. 2002. Automated on-line noninvasive optical glucose monitoring in a cell culture system. Appl. Spectrosc. 56:5157.
118. Kayser, K.,, N. Lin,, D. Allison,, L. Donahue, and, M. Caple. 2006. Cell line engineering methods for improving productivity. BioProcess Int. 4:S6–S13.
119. Keen, K. J., and , C. Hale. 1996. The use of serum-free medium for the production of functionally active humanized monoclonal antibody from NS0 mouse myeloma cells engineered using glutamine synthetase as a selectable marker. Cytotechnology 18:207217.
120. Kim, J. M.,, J.-S. Kim,, D.-H. Park,, H. S. Kang,, J. Yoon,, K. Baek, and, Y. Yoon. 2004. Improved recombinant gene expression in CHO cells using matrix attachment regions. J. Biotechnol. 107:95105.
121. Kim, N. S.,, S. J. Kim, and, G. M. Lee. 1998. Clonal variability within dihydrofolate reductase-mediated gene amplified Chinese hamster ovary cells: stability in the absence of selective pressure. Biotechnol. Bioeng. 60:679688.
122. Kirschweger, G. 2003. Crucell: biopharmaceuticals—as human as they get. Mol. Ther. 7:56.
123. Kisiday, J. D.,, B. Kurz,, M. A. DiMicco, and, A. J. Grodzinsky. 2005. Evaluation of medium supplemented with insulin-transferrin-selenium for culture of primary bovine calf chondrocyte in three-demensional hydrogel scaffolds. Tissue Eng. 11:141151.
124. Kobr, M.,, P. Chatellard, and, M. O. Imhof. 2008. Expression vector engineering for cell line development—new roles for “old” sequences. BioProcess. J. 7:1620.
125. Kohler, G., and , C. Milstein. 1975. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495497.
126. Kumar, N.,, P. Gammell,, P. Meleady,, M. Henry, and, M. Clynes. 2008. Differential protein expression following low temperature culture of suspension CHO-K1 cells. BMC Biotechnol. 8:4254.
127. Kunert, R.,, S. Wolbank,, M. Chang,, R. Voglauer,, N. Borth, and, H. Katinger. 2004. Control of key parameters in developing mammalian production clones. BioProcess Int. 2:5459.
128. Kunkel, J. P.,, D. C. H. Jan,, J. C. Jamieson, and, M. Butler. 1998. Dissolved oxygen concentration in serum-free continuous culture affects N-linked glycosylation of a monoclonal antibody. J. Biotechnol. 62:5571.
129. Kwaks, T. H.,, P. Barnett,, W. Hemrika,, T. J. Siersma,, R. G. Sewalt,, D. P. Satijn,, J. F. Brons,, R. Van Blokland,, P. Kwakman,, A. L. Kruckeberg,, A. Kelder, and, A. P. Otte. 2003. Identification of anti-repressor elements that confer high and stable protein production in mammalian cells. Nat. Biotechnol. 21:553558.
130. Kwaks, T. H., and , A. P. Otte. 2006. Employing epigenetics to augment the expression of therapeutic proteins in mammalian cells. Trends Biotechnol. 24:137142.
131. Laken, H. A., and , M. W. Leonard. 2001. Understanding and modulating apoptosis in industrial cell culture. Curr. Opin. Biotechnol. 12:175179.
132. Larson, T. M. 2002. Chemometric evaluation of on-line HPLC in mammalian cell cultures: analysis of amino acids and glucose. Biotechnol. Bioeng. 77:553563.
133. Lattenmayer, C.,, M. Loeschel,, K. Schriebl,, W. Stein-fellner,, T. Sterovsky,, E. Trummer,, K. Vorauer-Uhl,, D. Müller,, H. Katinger, and, R. Kunert. 2007. Protein-free transfection of CHO host cells with an IgG-fusion protein: selection and characterization of stable high-producers and comparison of conventionally transfected clones. Biotechnol. Bioeng. 96:11181126.
134. Lavric, V.,, I. Ofiteru, and, A. Woinaroschy. 2005. Sensitivity analysis of the fed-batch animal-cell bioreactor with respect to some control parameters. Biotechnol. Appl. Biochem. 41:2935.
135. Li, F.,, J. Z. Zhou,, X. Yang,, T. Tressel, and, B. Lee. 2006. Current therapeutic antibody production and process optimization. BioProcess. J. 4:1625.
136. Li, J.,, T. Sai,, M. Berger,, Q. Chao,, D. Davidson,, G. Deshmukh,, B. Drozdowski,, W. Ebel,, S. Harley,, M. Henry,, S. Jacob,, B. Kline,, E. Lazo,, F. Rotella,, E. Routhier,, K. Rudolph,, J. Sage,, J. Yao,, Y. Zhou,, M. Kavuru,, T. Bonfield,, M. J. Thomassen,, P. M. Sass,, N. C. Nicolaides, and, L. Grasso. 2006. Human antibodies for immunotherapy development generated via a human B cell hybridoma technology. Proc. Natl. Acad. Sci. USA 103:35573562.
137. Lim, A. C.,, J. Washbrook,, N. J. Titchener-Hooker, and, S. S. Farid. 2006. A computer-aided approach to compare the production economics of fed-batch and perfusion culture under uncertainty. Biotechnol. Bioeng. 93:687697.
138. Luo, Y., and , G. Chen. 2007. Combined approach of NMR and chemometrics for screening peptones used in the cell culture medium for the production of a recombinant therapeutic protein. Biotechnol. Bioeng. 97:16541659.
139. Ma, N.,, J. J. Chalmers,, J. G. Aunins,, W. Zhou, and, L. Xie. 2004. Quantitative studies of cell-bubble interactions and cell damage at different Pluronic F-68 and cell concentrations. Biotechnol. Prog. 20:11831191.
140. Maggon, K. 2007. Monoclonal antibody “gold rush.” Curr. Med. Chem. 14:19781987.
141. Maggon, K. 2009. Global monoclonal antibodies market review 2008 (world top ten MoAbs). (Online.) http://knol.google.com/k/krishan-maggon/global-monoclonal-antibodies-market.
142. Magil, S. G. 2005. Biopharmaceutical characterization techniques for early phase development of proteins. In Guide to Bioanalytical Advances. BioPharm Int. 18:S34S42.
143. Mahadevan, M. D. 2003. Bioreactor process selection for large-scale manufacture of monoclonal antibodies: tradeoffs and recommendations. BioProcess. J. 2:2531.
144. Majors, B. S.,, M. J. Betenbaugh, and, G. G. Chiang. 2007. Links between metabolism and apoptosis in mammalian cells: application for anti-apoptosis engineering. Metab. Eng. 9:473480.
145. Makrides, S. C. 1999. Components for vectors for gene transfer and expression in mammalian cells. Protein Expr. Purif. 17:183202.
146. Mandenius, C. F. 2004. Recent developments in the monitoring, modeling and control of biological production systems. Bioprocess Biosyst. Eng. 26:347351.
147. Manzi, A. E. 2008. Carbohydrates and their analysis, part two: glycoprotein characterization. BioProcess Int. 6:5067.
148. Merten, O. W. 1999. Safety issues of animal products used in serum-free medium. Dev. Biol. Stand. 99:167180.
149. Merten, O. W. 2002. Virus contaminations of cell cultures—a biotechnological view. Cytotechnology 39:91116.
150. Metcalfe, H.,, R. P. Field, and, S. J. Froud. 1994. The use of 2-hydroxy-2,4,6-cycloheptarin-1-one (tropolone) as a replacement for transferrin, p. 88–90. In R. E. Spier,, J. B. Griffiths, and , W. Berthold (ed.), Animal Cell Technology: Products of Today, Prospects of Tomorrow. Butterworth-Heinemann, Woburn, MA.
151. Meuwly, F.,, U. Weber,, T. Ziegler,, A. Gervais,, R. Mastrangeli,, C. Crisci,, M. Rossi,, A. Bernard,, U. von stockar, and, A. Kadouri. 2006. Conversion of a CHO cell culture from perfusion to fed-batch technology without altering product quality. J. Biotechnol. 123:106116.
152. Meyer, H. P.,, J. Brass,, C. Jungo,, J. Klein,, J. Wenger, and, R. Mommers. 2008. An emerging start for therapeutic and catalytic protein production. BioProcess Int. 6:S10S21.
153. Mirasol, F. 2008. Disposable bioreactor use grows in commercial production: a disposable future. ICIS Chem. Bus. 273(10). (Online.) http://www.icis.com/Articles/2008/03/10/9105767/Disposable-bioreactor-use-grows-in-commercial-production.html.
154. Mollet, M.,, N. Ma,, Y. Zhao,, R. Brodkey,, R. Taticek, and, J. J. Chalmers. 2004. Bioprocess equipment: characterization of energy dissipation rate and its potential to damage cells. Biotechnol. Prog. 20:14371448.
155. Mols, J.,, C. Peeters-Joris,, R. Wattiez,, S. N. Agathos, and, Y. J. Schneider. 2005. Recombinant interferon-gamma secreted by Chinese hamster ovary-320 cells cultivated in protein-free media is protected against extracellular proteolysis by the expression of natural protease inhibitors and by the addition of plant protein hydrolysates to the culture medium. In Vitro Cell. Dev. Biol. Anim. 41:8391.
156. Moore, A.,, J. Mercer,, G. Dutina,, C. J. Donahue,, K. D. Bauer,, J. P. Mather,, T. Etcheverry, and, T. Ryll. 1997. Effects of temperature shift on cell cycle, apoptosis, and nucleotide pools in CHO cell batch culture. Cytotechnology 23:4754.
157. Moreira, A. R. 2007. The evolution of protein expression and cell culture. BioPharm Int. 20:5668.
158. Mori, K.,, R. Kuni-Kamochi,, N. Yamane-Ohnuki,, M. Wakitani,, K. Yamano,, H. Imai,, Y. Kanda,, R. Niwa,, S. Iida,, K. Uchida,, K. Shitara, and, M. Satoh. 2004. Engineering Chinese hamster ovary cells to maximize effector function of produced antibodies using FUT8 siRNA. Biotechnol. Bioeng. 88:901908.
159. Moroney, S., and , A. Pluckthun. 2005. Modern antibody technology: the impact on drug development, p. 1147–1186. In J. Knablein (ed.), Modern Biopharma-ceuticals. Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim, Germany.
160. Morris, A. E.,, C.-C. Lee, and, J. N. Thomas. October, 2001. Expression augmenting sequence elements (ease) for eukaryotic expression system. U.S. patent 6,312,951.
161. Morrow, K. J. 2004. Antibody technology highlighted in Europe. Genet. Eng. Biotechnol. News 24(1).
162. Morrow, K. J. 2006. Disposable bioreactors gaining favor. Genet. Eng. Biotechnol. News 26(12).
163. Morrow, K. J., Jr. 2008. Method for maximizing antibody yields—new technologies could help usher in lower costs and increased availability. Genet. Eng. Biotechnol. News 28(12).
164. Mostafa, S., and , X. Gu. 2003. Strategies for improved dCO2 removal in large-scale fed-batch cultures. Biotechnol. Prog. 19:4551.
165. Muthing, J.,, S. E. Kemminer,, H. S. Conradt,, D. Sagi,, M. Nimtz,, U. Karst,, J. Peter-Katalinic. 2001. Effects of buffering conditions and culture pH on production rates and glycosylation of clinical Phase I anti-melanoma mouse IgG3 monoclonal antibody R24. Biotechnol. Bio-eng. 83:321334.
166. Nickoloff, J. A. 1995. Preface, p. v–vi. In J. A. Nickoloff (ed.), Electroporation Protocols for Microorganisms. Humana Press, Totowa, NJ.
167. Niloff, M. August 2008. Scale-up to 1000-liter perfusion cell culture in a single-use, stirred tank bioreactor. ISPE Boston Area Chapter Newsletter. International Society for Pharmaceutical Engineering, Tampa, FL.
168. Nyberg, G. B.,, R. R. Balcarcel,, B. D. Follstad,, G. Stephanopoulos, and, D. I. C. Wang. 1999. Metabolism of peptide amino acids by Chinese hamster ovary cells grown in a complex medium. Biotechnol. Bioeng. 62:324335.
169. Okonkowski, J.,, U. Balasubramanian,, C. Seamans,, S. Fries,, J. Zhang,, P. Salmon,, D. Robinson, and, M. Chartrain. 2007. Cholesterol delivery to NS0 cells: challenges and solutions in disposable liner low-density polyethylene-based bioreactors. J. Biosci. Bioeng. 103:5059.
170. Osman, J.,, J. Birch, and, J. Varley. 2001. The response of GS-NS0 myeloma cells to pH shifts and pH perturbations. Biotechnol. Bioeng. 75:6373.
171. Park, K. S.,, W. Seol,, H.-Y. Yang,, S. I. Lee,, S. K. Kim,, E.-J. Kwon,, Y.-H. Kim,, B. L. Roh, and, J. S. Seong. 2005. Identification and use of zinc finger transcription factors that increase production of recombinant proteins in yeast and mammalian cells. Biotechnol. Prog. 21:664670.
172. Pendlebury, D. 2008. Disposable systems in biopharmaceutical manufacturing. Fut. Pharm. Quarter 2:98100.
173. Percivia. 2008. Press release: DSM and Crucell announce record achievement in PER.C6 technology. June 16. Percivia, Cambridge, MA. (Online.) http://investors.crucell.com/C/132631/PR/200806/1227870_5_5.html.
174. Peshwa, M. V. 1999. Mammalian cell culture, p. 181–191. In A. L. Demain and, J. E. Davies (ed.), Manual of Industrial Microbiology and Biotechnology, 2nd ed. ASM Press, Washington, DC.
175. Pierce, L. N., and , P. W. Shabram. 2004. Scalability of a disposable bioreactor from 25 L–500 L run in perfusion mode with a CHO-based cell line: a tech review. BioProcess. J. 4:5156.
176. Pitti, R. M.,, S. A. Marsters,, M. Haak-Frendscho,, G. C. Osaka,, J. Mordenti,, S. M. Chamow, and, A. Ashkenazi. 1994. Molecular and biological properties of an interleukin-1 receptor immunoadhesin. Mol. Immunol. 31:13451351.
177. Portner, R.,, J. O. Schwabe, and, B. Frahm. 2004. Evaluation of selected control strategies for fed-batch cultures of a hybridoma cell line. Biotechnol. Appl. Biochem. 40:4755.
178. Rader, R. A. 2005. Biopharmaceutical terminology: what is a biopharmaceutical? BioExecutive Internat. Part 1, March; Part 2, May.
179. Rader, R. A. 2005. Biopharmaceutical Products in the US and European Markets, 4th ed. BioPlan Associates, Inc., Rockville, MD.
180. Rader, R. A. 2006. Biopharmaceutical approval review. Genet. Eng. Biotechnol. News 26(14).
181. Rader, R. A. 2008. Expression systems for process and product improvement. BioProcess Int. 6:S4S9.
182. Raju, T. S. 2003. Glycosylation variations with expression systems and their impact on biological activity of therapeutic immunoglobulins. BioProcess Int. 1:4453.
183. Raju, T. S.,, J. B. Briggs,, S. M. Borge, and, A. J. S. Jones. 2000. Species-specific variation in glycosylation of IgG: evidence for the species-specific sialylation and branch-specific galactosylation and importance for engineering recombinant glycoprotein therapeutics. Glycobiology 10:477486.
184. Ramelmeier, R. A.,, B. D. Kelley, and , C. Van Horn. 2001. Historical, current, and future trends for validating biological processes, p. 1–11. In B. D. Kelley and, R. A. Ramelmeier (ed.), Validation of Biopharmaceutical Manufacturing Processes. American Chemical Society, Washington, DC.
185. Rao, G.,, Y. Kostov,, A. Moreira,, D. Frey,, M. Hanson,, M. Jornitz,, O.-W. Reif,, R. Baumfalk, and , J. Qualitz. 2001. Non-invasive sensors as enablers of “smart” disposables. BioProcess Int. 7: S24S27.
186. Reichert, J. M. 2008. Monoclonal antibodies as innovative therapeutics. Curr. Pharm. Biotechnol. 9:423430.
187. Reichert, J. M.,, C. J. Rosensweig,, L. B. Faden, and, M. C. Dewitz. 2005. Monoclonal antibodies successes in the clinic. Nat. Biotechnol. 23:10731078.
188. Reik, A.,, Y. Zhou,, T. N. Collingwood,, L. Warfe,, V. Bartsevich,, Y. Kong,, K. A. Henning,, B. K. Fallentine,, L. Zhang,, X. Zhong,, Y. Jouvenot,, A. C. Jamieson,, E. J. Rebar,, C. C. Case,, A. Korman,, X.-Y. Li,, A. Black,, D. J. King, and, P. D. Gregory. 2007. Enhanced protein production by engineered zinc finger proteins. Biotechnol. Bioeng. 97:11801189.
189. Rendall, M. H.,, A. Maxwell,, D. Tatham,, P. Khan,, R. D. Gay,, R. C. Kallmeier,, J. R. Wayte, and, A. J. Racher. 2005. Transfection to manufacturing: reducing timelines for high yielding GS-CHO processes, p. 701–704. In F. Godia and, M. Fussenegger (ed.), Animal Cell Technology Meets Genetics. Springer, Dordrecht, The Netherlands.
190. Rodriguez, J.,, M. Spearman,, N. Huzel, and, M. Butler. 2005. Enhanced production of monomeric interferon-(β by CHO cells through the control of culture conditions. Biotechnol. Prog. 21:2230.
191. Rohwer, R. G. 1996. Analysis of risk to biomedical products developed from animal sources (with special emphasis on the spongiform encephalopathy agents, scrapie and BSE). Dev. Biol. Stand. 88:247256.
192. Ryu, J. S. 2001. Effects of cloned gene dosage on the response of recombinant CHO cells to hyperosmotic pressure in regard to cell growth and antibody production. Biotechnol. Prog. 17:993999.
193. Safdar, A., and , M. M. Cox. 2007. Baculovirus-expressed influenza vaccines: a novel technology for safe and expeditious vaccine production for human use. Expert Opin. Investig. Drugs 16:927934.
194. Sarkar, D., and , J. M. Modak. 2004. Algorithms with filters for optimal control problems in fed-batch bioreactors. Bioprocess Biosyst. Eng. 26:295306.
195. Sauer, P. W.,, J. E. Burky,, M. C. Wesson,, H. D. Ster-nard, and, L. Qu. 2000. A high-yielding, generic fed-batch cell culture process for production of recombinant antibodies. Biotechnol. Bioeng. 67:585597.
196. Schenerman, M. A.,, J. Casas-Finet,, M. J. Axley, and, C. N. Oliver. 2003. Characterization of alternatives to animal-derived raw materials. BioProcess Int. 1:4249.
197. Schenerman, M. A.,, B. R. Sunday,, S. Kozlowski,, K. Webber,, H. Gazzano-Santoro, and, A. Mire-Sluis. 2001. CMC strategy forum report—analysis and structure characterization of monoclonal antibodies. BioProcess Int. 2:4252.
198. Schimke, R. T.,, D. S. Roos, and, P. C. Brown. 1987. Amplification of genes in somatic mammalian cells. Methods Enzymol. 151:85104.
199. Schlaeger, E. J. 1996. The protein hydrolysate, Primatone RL, is a cost-effective multiple growth promoter of mammalian cell culture in serum containing and serum-free media and displays anti-apoptosis properties. J. Immunol. Methods 194:191199.
200. Schlatter, S.,, S. H. Stanfield,, D. M. Dinnis,, A. J. Racher,, J. R. Birch, and, D. C. James. 2005. On the optimal ratio of heavy to light chain genes for efficient recombinant antibody production by CHO cells. Biotechnol. Prog. 21:122133.
201. Schonfelder, M., and , P. Schlenke. 2007. Keep the whole process in view: from stable cell lines to robust manufacturing processes. BioProcess Int. 5:7077.
202. Schroder, M.,, K. Matischak, and, P. Friedl. 2004. Serum- and protein-free media formulations for the Chinese hamster ovary cell line DUKXB11. J. Biotechnol. 108:279292.
203. Scott, C. 2008. In the bioprocess zone: the state of the art is science. In Bio International Convention Preshow Planner. BioProcess Int. 6:S8-S19.
204. Scott, C. 2008. Biotech leads a revolution in vaccine manufacturing. BioProcess Int. 6:S12S18.
205. Scott, C.,, S. A. Montgomery, and, L. J. Rosin. 2007. Genetic engineering leads to microbial, animal cell, and transgenic expression systems. In Bio International Convention: Official Pre-Event Planner. BioProcess Int. 5: S27S34.
206. Seamans, T. C.,, S. Fries,, A. Beck,, T. Wurch,, S. Chenu,, C. Chan,, M. Ushio,, J. Bailey,, A. Kejariwal,, C. Ranucci,, N. Villani,, S. Ozuna,, L. Goetsch,, N. Corvaia,, P. Salmon,, D. Robinson, and, M. Chartrain. 2008. Cell cultivation process transfer and scale-up in support of production of early clinical supplies of an anti-IGF-1R antibody, part 2. BioProcess Int. 6:3442.
207. Selexis SA and Artelis SA. 2008. Press release: Artelis and Selexis report record antibody production levels in CHO cells of over 31 grams per liter. Sept. 20. Artelis SA, Brussels, Belgium. (Online.) http://www.artelis.be/uploads//ARTELISSELEXIS%20SEPT08.pdf.
208. Senger, R. S., and , M. N. Karim. 2003. Effect of shear stress on intrinsic CHO culture state and glycosylation of recombinant tissue-type plasminogen activator protein. Biotechnol. Prog. 19:11991209.
209. Senger, R. S., and , M. N. Karim. 2007. Optimization of fed-batch parameters and harvest time of CHO cell cultures for a glycosylated product with multiple mechanism of inactivation. Biotechnol. Bioeng. 98:378390.
210. Seth, G.,, R. S. Mclvor, and , W.-S. Hu. 2006. 17(β-Hydroxysteroid dehydrogenase type 7 (Hsd17b7) reverts cholesterol auxotrophy in NS0 cells. J. Biotechnol. 121:241252.
211. Seth, G.,, R. J. Philp,, A. Lau,, K. Y. Jiun,, M. Yap, and , W.-S. Hu. 2007. Molecular portrait of high productivity in recombinant NS0 cells. Biotechnol. Bioeng. 97:933951.
212. Sharfstein, S. T. 2008. Advances in cell culture process development: tools and techniques for improving cell line development and process optimization. Biotechnol. Prog. 24:727734.
213. Sheeley, D. M.,, B. M. Merrill, and, L. C. E. Taylor. 1997. Characterization of monoclonal antibody glycosylation: comparison of expression systems and identification of terminal a-linked galactose. Anal. Biochem. 247:102110.
214. Shulman, M.,, C. D. Wilde, and, G. A. Kohler. 1978. A better cell line for making hybridoma secreting specific antibodies. Nature 276:269270.
215. Simmons, L. C.,, D. Reilly,, L. Klimowski,, T. S. Raju,, G. Meng,, P. Sims,, K. Hong,, R. L. Shields,, L. A. Damico, and, P. Rancatore. 2002. Expression of full-length immunoglobu-lins in Escherichia coli: rapid and efficient production of agly-cosylated antibodies. J. Immunol. Methods 263:133147.
216. Simpson, N. H.,, R. P. Singh,, A. Perani,, C. Goldenzon, and , M. Al-Rubeai. 1998. In hybridoma cultures, deprivation of any single amino acid leads to apoptotic death, which is suppressed by the expression of the bcl-2 gene. Biotechnol. Bioeng. 59:9098.
217. Sinacore, M. S.,, T. S. Charlebois,, S. Harrison,, S. Brennan,, T. Richards,, M. Hamilton,, S. Scott,, S. Brodeur,, P. Oakes,, M. Leonard,, M. Switzer,, A. Anagnostopoulos,, B. Foster,, A. Harris,, M. Jankowski,, M. Bond,, S. Martin, and, S. R. Adamson. 1996. CHO DUKX cell lineages preadapted to growth in serum-free suspension culture enable rapid development of cell culture processes for the manufacture of recombinant proteins. Biotechnol. Bioeng. 52:518528.
218. Sinclair, A. 2008. Disposable bioreactors: the next generation. BioPharm Int. 21:3840.
219. Sinclair, A. 2009. An industry in transition. BioProcess Int. 7:S1.
220. Sinclair, A., and , M. Monge. 2002. Quantitative economic evaluation of single use disposables in bioprocessing. Pharm. Eng. 22:2034.
221. Smales, C. M.,, D. M. Dinnis,, S. H. Stansfield,, D. E. Alete,, E. A. Sage,, J. R. Birch,, A. J. Racher,, C. T. Marshall, and, D. C. James. 2004. Comparative proteomic analysis of GS-NS0 murine myeloma cell lines with varying recombinant monoclonal antibody production rate. Biotechnol. Bioeng. 88:474488.
222. Spens, E., and , L. Haggstrom. 2005. Defined protein-free NS0 myeloma cell cultures: stimulation of proliferation by conditioned medium factors. Biotechnol. Prog. 21:8795.
223. Stein, A. 2007. Decreasing variability in your cell culture. Biotechniques 43:228229.
224. Stockwin, L. H., and , S. Holmes. 2003. Antibodies as therapeutic agents: vive la renaissance. Expert Opin. Biol. Ther. 3:11331152.
225. Sung, Y. H.,, S. W. Lim,, J. Y. Chun, and, J. M. Lee. 2004. Yeast hydrolysate as a low-cost additive to serum-free medium for the production of human thrombopoietin in suspension cultures of Chinese hamster ovary cells. Appl. Microbiol. Biotechnol. 63:527536.
226. Swartz, J. R. 2001. Advances in Escherichia coli production of therapeutic proteins. Curr. Opin. Biotechnol. 12:195201.
227. Thalen, M. 2008. The next generation of biologicals and their production systems. BioProcess Int. 6:S20S23.
228. Tsao, Y. S.,, S. L. Gould, and, D. K. Robinson. 2000. Animal cell culture media, p. 31–35. In R. E. Spier (ed.), Encyclopedia of Cell Technology. John Wiley & Sons, Inc., Hoboken, NJ.
229. Umana, P.,, P. Jean-Mairet,, R. Moudry,, H. Amstutz, and, J. E. Bailey. 1999. Engineered glycoforms of an anti-neuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat. Biotechnol. 17:176180.
230. Urnov, F. D.,, J. C. Miller,, Y.-L. Lee,, C. M. Beausejour,, J. M. Rock,, S. Augustus,, A. C. Jamieson,, M. H. Porteus,, P. D. Gregory, and, M. C. Holmes. 2005. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 435:646651.
231. Varley, J., and , J. R. Birch. 1999. Reactor design for large-scale suspension animal cell culture. Cytotechnology 29:177205.
232. Vicki, G. 2005. Disposable bioreactors become standard fare. Genet. Eng. Biotechnol. News 25(14).
233. Voisard, D.,, F. Meuwly,, P. A. Ruffieux,, G. Baer, and, A. Kadouri. 2003. Potential of cell retention techniques for large-scale high-density perfusion culture of suspended mammalian cells. Biotechnol. Bioeng. 82:751765.
234. Walowitz, J. L.,, R. M. Fike, and, D. W. Jayme. 2003. Efficient lipid delivery to hybridoma culture by use of cyclodextrin in a novel granulated dry-form medium technology. Biotechnol. Prog. 19:6468.
235. Walsh, G. 2003. Pharmaceuticals, biologics and bio-pharmaceuticals. In G. Walsh (ed.), Biopharmaceuticals: Biochemistry and Biotechnology, 2nd ed. John Wiley & Sons, Inc., Hoboken, NJ.
236. Walsh, G. 2005. Biopharmaceuticals; recent approvals and likely directions. Trends Biotechnol. 23:553558.
237. Walsh, G. 2006. Biopharmaceutical benchmark 2006. Nat. Biotechnol. 24:769776.
238. Walsh, G. 2008. Biopharmaceuticals: approval trends in 2007. BioPharm Int. 5:5265.
239. Ward, M.,, L. Cherry,, D. C. Victoria,, B. P. Fox,, J. A. Fox,, D. L. Wong,, H. J. Meerman,, J. P. Pucci,, R. B. Fong,, M. H. Heng,, N. Tsurushita,, C. Gieswein,, M. Park, and, H. Wang. 2004. Characterization of humanized antibodies secreted by Aspergillus niger. Appl. Environ. Microbiol. 70:25672576.
240. Wayte, M.,, R. Boraston,, H. Bland,, J. Varley, and, M. Brown. 1997. pH: effects on growth and productivity of cell lines producing monoclonal antibodies: control in large-scale fermentors. Genet. Eng. Biotechnol. News 17:125132.
241. Weaver, J. C. 1995. Electroporation theory: concepts and mechanisms, p. 1–26. In J. A. Nickoloff (ed.), Elec-troporation Protocols for Microorganisms. Humana Press, Totowa, NJ.
242. Whitford, W. G. 2004. Large-scale exogenous protein production in higher animal cells. In S. R. Parekh (ed.), The GMO Handbook: Genetically Modified Animals, Microbes, and Plants in Biotechnology. Humana Press, Totowa, NJ.
243. Whitford, W. G. 2005. Supplementation of animal cell culture media. BioProcess Int. 3:S28S36.
244. Whitford, W. G. 2006. Fed-batch mammalian cell culture in bioproduction. BioProcess Int. 4:3044.
245. Wildt, S., and , T. U. Gerngross. 2005. The humanization of N-glycosylation pathways in yeast. Nat. Rev. Microbiol. 3:119128.
246. Wilson, G. 2007. Evaluation of a novel micro-bioreactor system for cell culture optimization, p. 611. In R. Smith (ed.), Cell Technology for Cell Products. Proceedings of the 19th ESACT Meeting, Harrogate, UK. Springer, Dordrecht, The Netherlands.
247. Winder, R. 2005. Cell culture changes gear. Chem. Ind. October:1820.
248. Wong, D. C. F.,, K. T. K. Wong,, L. T. Goh,, C. K. Heng, and, M. G. S. Yap. 2005. Impact of dynamic online fed-batch strategies on metabolism, productivity and N-glycosylation quality in CHO cell cultures. Biotechnol. Bioeng. 89:164177.
249. Wong, V. T.,, K. W. Ho, and, M. G. S. Yap. 2004. Evaluation of insulin-mimetic trace metals as insulin replacements in mammalian cell cultures. Cytotechnology 45:107115.
250. Wurm, F. M. 2004. Production of recombinant protein therapeutics in cultivated mammalian cells. Nat. Biotechnol. 22:13931398.
251. Wurm, F. M., and , A. R. Bernard. 1999. Large scale transient expression in mammalian cells for recombinant protein production. Curr. Opin. Biotechnol. 10:156159.
252. Xcellerex. 2008. Application brief: scale-up to 1000-L perfusion cell culture in a disposable stirred-tank biore-actor. April 7. Xcellerex, Marlborough, MA. (Online.) www.xcellerex.com/pdf/perfusion.pdf.
253. Xie, L., and , D. I. C. Wang. 1994. Application of improved stoichiometric model in medium design and fed-batch cultivation of animal cells in bioreactor. Cyto-technology 15:1729.
254. Xie, L., and , D. I. C. Wang. 1996. High cell density and high monoclonal antibody production through medium design and rational control in a bioreactor. Biotechnol. Bioeng. 51:725729.
255. Xie, L., and , D. I. C. Wang. 1997. Integrated approaches to the design of media and feeding strategies for fed-batch cultures of animal cells. Trends Biotechnol. 15:109113.
256. Yamane-Ohnuki, N.,, S. Kinoshita,, M. Inoue-Urakubo,, M. Kusunoki,, S. Iida,, R. Nakano,, M. Wakitani,, R. Niwa,, M. Sakurada,, K. Uchida,, K. Shitara, and, M. Satoh. 2004. Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity. Biotechnol. Bioeng. 87:614622.
257. Yang, J.,, C. Lu,, B. Stasny,, J. Henley,, W. Guinto,, C. Gonzalez,, M. Fung,, B. Collopy,, M. Benjamino,, J. Gangi,, M. Hanson, and, E. Ille. 2007. Fed-batch bioreac-tor process scale-up from 3-L to 2,500-L scale for monoclonal antibody production from cell culture. Biotechnol. Bioeng. 98:141154.
258. Yeung, K. S.,, M. Hoare,, N. F. Thornhill,, T. Williams, and, J. D. Vaghjiani. 1999. Near-infrared spectroscopy for bioprocess monitoring and control. Biotechnol. Bioeng. 63:684693.
259. Yoon, S. O.,, M. M. Kim,, S. J. Park,, D. Kim,, J. Chung, and, A. S. Chung. 2002. Selenite suppresses hydrogen peroxide-induced cell apoptosis through inhibition of ASK1/JNK and activation of PI3-K/Akt pathways. FASEB J. 16:111113.
260. Zang, M.,, H. Trautmann,, C. Gandor,, F. Messi,, F. Asselbergs,, C. Leist,, A. Fiechter, and, J. Reiser. 1995. Production of recombinant protein in Chinese hamster cells using a protein-free cell culture medium. Bio/Technology 13:389392.
261. Zeng, A., and , J. Bi. 2006. Cell culture kinetics and modeling, p. 299–348. In S. S. Ozturk and, W.-S. Hu (ed.), Cell Culture Technology for Pharmaceutical and Cell-Based Therapies (Biotechnology and Bioprocessing Series). CRC Press, Boca Raton, FL.
262. Zhang, F.,, M. A. Saarinen,, L. J. Itle,, S. C. Lang,, D. W. Murhammer, and, R. J. Linhardt. 2002. The effect of dissolved oxygen (DO) concentration on the glyco-sylation of recombinant protein produced by the insect cell-baculovirus expression systems. Biotechnol. Bioeng. 77:219224.
263. Zhang, J., and , D. Robinson. 2005. Development of animal-free, protein-free and chemically-defined media for NS0 cell culture. Cytotechnology 48:5974.
264. Zhang, J.,, D. Robinson, and, P. Salmon. 2006. A novel function for selenium in biological system: selenite as a highly effective iron carrier for Chinese hamster ovary cell growth and monoclonal antibody production. Biotechnol. Bioeng. 95:11881197.
265. Zhang, L.,, H. Shen, and, Y. Zhang. 2004. Fed-batch culture of hybridoma cells in serum-free medium using an optimized feeding strategy. J. Chem. Technol. Biotechnol. 79:171181.
266. Zhao, D.,, R. Fike,, B. Naumovich, and, M. Stramaglia. 2008. Improving protein production in CHO cells. In Guide to Protein Production. BioPharm Int. 21:S22S27.
267. Zhu, M. M.,, A. Goyal,, D. L. Rank,, S. K. Gupta,, T. V. Boom, and, S. S. Lee. 2005. Effects of elevated pCO2 and osmolality on growth of CHO cells and production of antibody-fusion protein B1: a case study. Biotechnol. Prog. 21:7077.


Generic image for table

FDA-approved monoclonal antibody products

Citation: Zhang J. 2010. Mammalian Cell Culture for Biopharmaceutical Production, p 157-178. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch12

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error