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Engineering Mammalian Cells for Recombinant Monoclonal Antibody Production

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Cell Line Development

Part of the book series: Cell Engineering ((CEEN,volume 6))

Abstract

Recombinant monoclonal antibodies represent one of the most important classes of new therapeutic entities. They are increasingly used to treat a variety of diseases, including several cancers. Large-scale commercial manufacture of recombinant antibodies is dependent upon the development of high-yielding production processes that are underpinned by expression of antibody genes in heterologous host cells – most frequently mammalian cells in culture. In this chapter we review recent advances in gene expression technologies that enable sustained high-level production of recombinant monoclonal antibodies in mammalian cells. We describe improvements in antibody expression vector design and recent attempts to improve the cellular process of antibody production through directed cell engineering.

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References

  • Aldrich TL, Viaje A, Morris AE (2003) EASE vectors for rapid stable expression of recombinant antibodies. Biotechnol Prog 19:1433–1438

    Article  PubMed  CAS  Google Scholar 

  • Alete DE, Racher AJ, Birch JR, Stansfield SH, James DC, Smales M (2005) Proteomic analysis of enriched microsomal fractions from GS-NS0 murine myeloma cells with varying secreted recombinant monoclonal antibody productivities. Proteomics 5:4689–4704

    Article  PubMed  CAS  Google Scholar 

  • Antoniou M, Harland L, Mustoe T, Williams S, Holdstock J, Yague E, Mulcahy T, Griffiths M, Edwards S, Ioannou PA, Mountain A, Crombie R (2003) Transgenes encompassing dual-promoter CpG islands from the human TBP and HNRPA2B1 loci are resistant to heterochromatin-mediated silencing. Genomics 82:269–279

    Article  PubMed  CAS  Google Scholar 

  • Barnes LM, Bently CM, Dickson AJ (2001) Characterization of the stability of recombinant protein production in the GS-NS0 expression system. Biotechnol Bioeng 73:261–270

    Article  PubMed  CAS  Google Scholar 

  • Barnes LM, Bently CM, Dickson AJ (2003) Stability of protein production from recombinant mammalian cells. Biotechnol Bioeng 81:631–639

    Article  PubMed  CAS  Google Scholar 

  • Barnes LM, Bentley CM, Dickson AJ (2004) Molecular definition of predictive indicators of stable protein expression in recombinant NS0 myeloma cells. Biotechnol Bioeng 85:115–121

    Article  PubMed  CAS  Google Scholar 

  • Barnes LM, Moy N, Dickson AJ (2006) Phenotypic variation during cloning procedures: analysis of the growth behavior of clonal cell lines. Biotechnol Bioeng 94:530–537

    Article  PubMed  CAS  Google Scholar 

  • Barnes LM, Bentley CM, Moy N, Dickson AJ (2007) Molecular analysis of successful cell line selection in transfected GS-NS0 myeloma cells. Biotechnol Bioeng 96:337–348

    Article  PubMed  CAS  Google Scholar 

  • Bebbington CR, Renner G, Thomson S, King D, Abrams D, Yarranton GT (1992) High-level expression of a recombinant antibody from myeloma cells using a glutamine-synthetase gene as an amplifiable selectable marker. Biotechnology 10:169–175

    Article  PubMed  CAS  Google Scholar 

  • Becker E, Florin L, Pfizenmaier K, Kaufmann H (2008) An XBP-1 dependent bottle-neck in production of IgG subtype antibodies in chemically defined serum-free Chinese hamster ovary (CHO) fed-batch processes. J Biotechnol 135:217–223

    Article  PubMed  CAS  Google Scholar 

  • Benton T, Chen T, McEntee M, Fox B, King D, Crombie R, Thomas TC, Bebbington C (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 38:43–46

    Article  PubMed  CAS  Google Scholar 

  • Betenbaugh MJ, Ailor E, Whiteley E, Hinderliter P, Hsu TA (1996) Chaperone and foldase expression in the baculovirus-insect cell expression. Cytotechnology 20:149–159

    Article  CAS  Google Scholar 

  • Bianchi AA, McGrew JT (2003) High-level expression of full-length antibodies using trans-complementing expression vectors. Biotechnol Bioeng 84:439–444

    Article  PubMed  CAS  Google Scholar 

  • Bibila T, Flickinger MC (1991) A structured model for monoclonal-antibody synthesis in exponentially growing and stationary phase hybridoma cells. Biotechnol Bioeng 37:210–226

    Article  PubMed  CAS  Google Scholar 

  • Bibila T, Flickinger MC (1992) Use of a structured kinetic-model of antibody-synthesis and secretion for optimization of antibody-production systems 2. Transient analysis. Biotechnol Bioeng 37:262–272

    Article  Google Scholar 

  • Birch JR, Racher AJ (2006) Antibody production. Adv Drug Deliv Rev 58:671–685

    Article  PubMed  CAS  Google Scholar 

  • Borth N, Strutzenberger K, Kunert R, Steinfellner W, Katinger H (1999) Analysis of changes during subclone development and ageing of human antibody-producing heterohybridoma cells by northern blot and flow cytometry. J Biotechnol 67:57–66

    Article  PubMed  CAS  Google Scholar 

  • Borth N, Mattanovich D, Kunert R, Katinger H (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 21:106–111

    Article  PubMed  CAS  Google Scholar 

  • Boshart M, Weber F, Jahn G, Dorsch-Hasler H, Fleckenstein B, Schaffner W (1985) A very strong enhancer is located upstream of an immediate early gene of human cytomegalovirus. Cell 41:521–530

    Article  PubMed  CAS  Google Scholar 

  • Brewer JW, Hendershot LM (2005) Building an antibody factory: a job for the unfolded protein response. Nat Immunol 6:23–29

    Article  PubMed  CAS  Google Scholar 

  • Brezinsky SC, Chiang GG, Szilvasi A, Mohan S, Shapiro RI, MacLean A, Sisk W, Thill G (2003) A simple method for enriching populations of transfected CHO cells for cells of higher specific productivity. J Immunol Methods 277:141–155

    Article  PubMed  CAS  Google Scholar 

  • Brown ME, Renner G, Field RP, Hassell T (1992) Process development for the production of recombinant antibodies using the glutamine synthetase (GS) system. Cytotechnology 9:231–236

    Article  PubMed  CAS  Google Scholar 

  • Browne SM, Al-Rubeai M (2007) Selection methods for high-producing mammalian cell lines. Trends Biotechnol 25:425–432

    Article  PubMed  CAS  Google Scholar 

  • Carton JM, Sauerwald T, Hawley-Nelson P, Morse B, Peffer N, Beck H, Lu J, Cotty A, Amegadzie B, Sweet R (2007) Codon engineering for improved antibody expression in mammalian cells. Protein Expr Purif 55:279–286

    Article  PubMed  CAS  Google Scholar 

  • Cockett MI, Bebbington CR, Yarranton GT (1990) High-level expression of tissue inhibitor of metalloproteinases in Chinese hamster ovary cells using glutamine-synthetase gene amplification. Biotechnology 8:662–667

    Article  PubMed  CAS  Google Scholar 

  • Couture ML, Heath CA (1995) Relationship between loss of heavy chains and the appearance of nonproducing hybridomas. Biotechnol Bioeng 47:270–275

    Article  PubMed  CAS  Google Scholar 

  • de Felipe P, Martin V, Cortes ML, Ryan M, Izquierdo M (1999) Use of the 2A sequence from foot-and-mouth disease virus in the generation of retroviral vectors for gene therapy. Gene Ther 6:198–208

    Article  PubMed  CAS  Google Scholar 

  • de Felipe P, Luke GA, Hughes LE, Gani D, Halpin C, Ryan MD (2006) E unum pluribus: multiple proteins from a self-processing polyprotein. Trends Biotechnol 24:68–75

    Article  PubMed  CAS  Google Scholar 

  • Derouazi M, Martinet D, Besuchet Schmutz N, Flaction R, Wicht M, Bertschinger M, Hacker DL, Beckmann JS, Wurm FM (2006) Genetic characterization of CHO production host DG44 and derivative recombinant cell lines. Biochem Biophys Res Commun 340:1069–1077

    Article  PubMed  CAS  Google Scholar 

  • Dillon N, Festenstein R (2002) Unravelling heterochromatin: competition between positive and negative factors regulates accessibility. Trends Genet 18:252–258

    Article  PubMed  CAS  Google Scholar 

  • Dinnis DM, James DC (2005) Engineering mammalian cell factories for improved recombinant monoclonal antibody production: lessons from nature? Biotechnol Bioeng 91:180–189

    Article  PubMed  CAS  Google Scholar 

  • Dinnis DM, Stansfield SH, Schlatter S, Smales CM, Alete D, Birch JR, Racher AJ, Marshall CT, Nielsen LK, James DC (2006) Functional proteomic analysis of GS-NS0 murine myeloma cell lines with varying recombinant monoclonal antibody production rate. Biotechnol Bioeng 94:830–841

    Article  PubMed  CAS  Google Scholar 

  • Donnelly ML, Luke G, Mehrotra A, Li X, Hughes LE, Gani D, Ryan MD (2001) Analysis of the aphthovirus 2A/2B polyprotein ‘cleavage’ mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal ‘skip’. J Gen Virol 82:1013–1025

    PubMed  CAS  Google Scholar 

  • Dul JL, Aviel S, Melnick J, Argon Y (1996) Ig light chains are secreted predominantly as monomers. J Immunol 157:2969–2975

    PubMed  CAS  Google Scholar 

  • Fagioli C, Mezghrani A, Sitia R (2001) Reduction of interchain disulfide bonds precedes the dislocation of Ig-μ chains from the endoplasmic reticulum to the cytosol for proteasomal degradation. J Biol Chem 276:40962–40967

    Article  PubMed  CAS  Google Scholar 

  • Fang J, Qian JJ, Yi S, Harding TC, Tu GH, VanRoey M, Jooss K (2005) Stable antibody expression at therapeutic levels using the 2A peptide. Nat Biotechnol 23:584–590

    Article  PubMed  CAS  Google Scholar 

  • Fang J, Yi S, Simmons A, Tu GH, Nguyen M, Harding TC, VanRoey M, Jooss K (2007) An antibody delivery system for regulated expression of therapeutic levels of monoclonal antibodies in vivo. Mol Ther 15:1153–1159

    PubMed  CAS  Google Scholar 

  • Fann CH, Guarna MM, Kilburn DG, Piret JM (1999) Relationship between recombinant activated protein C secretion rates and mRNA levels in baby hamster kidney cells. Biotechnol Bioeng 63:464–472

    Article  PubMed  CAS  Google Scholar 

  • Flickinger MC, Goebel NK, Bibila T, Boycejacino S (1992) Evidence for posttranscriptional stimulation of monoclonal-antibody secretion by L-glutamine during slow hybridoma growth. J Biotechnol 22:201–226

    Article  PubMed  CAS  Google Scholar 

  • Foecking MK, Hofstetter H (1986) Powerful and versatile enhancer-promoter unit for mammalian expression vectors. Gene 45:101–105

    Article  PubMed  CAS  Google Scholar 

  • Fouser LA, Swanberg SL, Lin BY, Benedict M, Kelleher K, Cumming DA, Riedel GE (1992) High-level expression of a chimeric antiganglioside Gd2 antibody – genomic kappa sequences improve expression in Cos and CHO Cells. Biotechnology 10:1121–1127

    Article  PubMed  CAS  Google Scholar 

  • Fussenegger M, Moser S, Bailey JE (1998) pQuattro vectors allow one-step multigene metabolic engineering and auto-selection of quattrocistronic artificial mammalian operons. Cytotechnology 28:229–235

    Article  PubMed  CAS  Google Scholar 

  • Gass JN, Gifford NM, Brewer JW (2002) Activation of an unfolded protein response during differentiation of antibody-secreting B cells. J Biol Chem 277:49047–49054

    Article  PubMed  CAS  Google Scholar 

  • Girod PA, Zahn-Zabal M, Mermod N (2005) Use of the chicken lysozyme 5′ matrix attachment region to generate high producer CHO cell lines. Biotechnol Bioeng 91:1–11

    Article  PubMed  CAS  Google Scholar 

  • Gomord V, Sourrouille C, Fitchette AC, Bardor M, Pagny S, Lerouge P, Faye L (2004) Production and glycosylation of plant-made pharmaceuticals: the antibodies as a challenge. Plant Biotechnol J 2:83–100

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez R, Andrews BA, Asenjo JA (2001) Metabolic control analysis of monoclonal antibody synthesis. Biotechnol Prog 17:217–226

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez R, Andrews BA, Asenjo JA (2002) Kinetic model of BiP- and PDI-mediated protein folding and assembly. J Theor Biol 214:529–537

    Article  CAS  Google Scholar 

  • Goto Y, Hamaguchi K (1981) Formation of the intrachain disulfide bond in the constant fragment of the immunoglobulin light chain. J Mol Biol 146:321–340

    Article  PubMed  CAS  Google Scholar 

  • Gu MB, Kern JA, Todd P, Kompala DS (1992) Effect of Amplification of dhfr and lac Z genes on growth and beta-galactosidase expression in suspension-cultures of recombinant CHO cells. Cytotechnology 9:237–245

    Article  PubMed  CAS  Google Scholar 

  • Gurtu V, Yan G, Zhang G (1996) IRES bicistronic expression vectors for efficient creation of stable mammalian cell line. Biochem Biophys Res Commun 229:295–298

    Article  PubMed  CAS  Google Scholar 

  • Halpin C, Cooke SE, Barakate A, El Amrani A, Ryan MD (1999) Self-processing 2A polyproteins – a system for co-ordinates expression of multiple proteins in transgenic plants. Plant J 17:453–459

    Article  PubMed  CAS  Google Scholar 

  • Ho Y, Varley J, Mantalaris A (2006) Development and analysis of a mathematical model for antibody-producing GS-NS0 cells under normal and hyperosmotic culture conditions. Biotechnol Prog 22:1560–1569

    PubMed  CAS  Google Scholar 

  • Houdebine LM, Attal J (1999) Internal ribosome entry sites (IRESs): reality and use. Transgenic Res 8:157–177

    Article  PubMed  CAS  Google Scholar 

  • Hsu TA, Watson S, Eiden JJ, Betenbaugh MJ (1996) Rescue of immunoglobulins from insolubility is facilitated by PDI in the baculovirus expression system. Protein Expr Purif 7:281–288

    Article  PubMed  CAS  Google Scholar 

  • Huang Y, Li Y, Wang YG, Gu X, Wang Y, Shen BF (2007) An efficient and targeted gene integration for high-level antibody expression. J Immunol Methods 322:28–39

    Article  PubMed  CAS  Google Scholar 

  • Jefferis R (2005) Glycosylation of recombinant antibody therapeutics. Biotechnol Prog 21:11–16

    Article  PubMed  CAS  Google Scholar 

  • Jiang Z, Huang Y, Sharfstein ST (2006) Regulation of recombinant monoclonal antibody production in chinese hamster ovary cells: a comparative study of gene copy number, mRNA level, and protein expression. Biotechnol Prog 22:313–318

    Article  PubMed  CAS  Google Scholar 

  • Jones D, Kroos N, Anema R, Van Montfort B, Vooys A, Van Der Kraats S, Van Der Helm E, Smits S, Schouten J, Brouwer K, Lagerwerf F, van Berkel P, Opstelten DJ, Logtenberg T, Bout A (2003) High-level expression of recombinant IgG in the human cell line per.c6. Biotechnol Prog 19:163–168

    Article  PubMed  CAS  Google Scholar 

  • Kalwy S, Rance J, Young R (2006) Toward more efficient protein expression: keep the message simple. Mol Biotechnol 34:151–156

    Article  PubMed  CAS  Google Scholar 

  • Kaufman RJ, Wasley LC, Spiliotes AJ, Gossels SD, Latt SA, Larsen GR, Kay RM (1985) Coamplification and coexpression of human tissue-type plasminogen activator and murine dihydrofolate reductase sequences in Chinese hamster ovary cells. Mol Cell Biol 5:1750–1759

    PubMed  CAS  Google Scholar 

  • Kaufman RJ, Davies MV, Wasley LC, Michnick D (1991) Improved vectors for stable expression of foreign genes in mammalian cells by use of the untranslated leader sequence from EMC virus. Nucleic Acids Res 19:4485–4490

    Article  PubMed  CAS  Google Scholar 

  • Khoo SH, Falciani F, Al-Rubeai M (2007) A genome-wide transcriptional analysis of producer and non-producer NS0 myeloma cell lines. Biotechnol Appl Biochem 47:85–95

    Article  PubMed  CAS  Google Scholar 

  • Kim HS, Lee GM (2007) Differences in optimal pH and temperature for cell growth and antibody production between two Chinese hamster ovary clones derived from the same parental clone. J Microbiol Biotechnol 17:712–720

    PubMed  CAS  Google Scholar 

  • Kim NS, Kim SJ, Lee GM (1998a) Clonal variability within dihydrofolate reductase-mediated gene amplified Chinese hamster ovary cells: stability in the absence of selective pressure. Biotechnol Bioeng 60:679–688

    Article  PubMed  CAS  Google Scholar 

  • Kim SJ, Kim NS, Ryu CJ, Hong HJ, Lee GM (1998b) Characterization of chimeric antibody producing CHO cells in the course of dihydrofolate reductase-mediated gene amplification and their stability in the absence of selective pressure. Biotechnol Bioeng 58:73–84

    Article  PubMed  CAS  Google Scholar 

  • Kim NS, Byun TH, Lee GM (2001) Key determinants in the occurrence of clonal variation in humanized antibody expression of cho cells during dihydrofolate reductase mediated gene amplification. Biotechnol Prog 17:69–75

    Article  PubMed  CAS  Google Scholar 

  • Kim JM, Kim JS, Park DH, Kang HS, Yoon J, Baek K, Yoon Y (2004) Improved recombinant gene expression in CHO cells using matrix attachment regions. J Biotechnol 170:95–105

    Article  CAS  Google Scholar 

  • Kito M, Itami S, Fukano Y, Yamana K, Shibui T (2002) Construction of engineered CHO strains for high-level production of recombinant proteins. Appl Microbiol Biotechnol 60:442–448

    Article  PubMed  CAS  Google Scholar 

  • Koduri RK, Miller JT, Thammana P (2001) An efficient homologous recombination vector pTV(I) contains a hot spot for increased recombinant protein expression in Chinese hamster ovary cells. Gene 280:87–95

    Article  PubMed  CAS  Google Scholar 

  • Kozak M (1999) Initiation of translation in prokaryotes and eurkaryotes. Gene 234:187–208

    Article  PubMed  CAS  Google Scholar 

  • Kromenaker SJ, Srienc F (1994) Stability of producer hybridoma cell lines after cell sorting: a case study. Biotechnol Prog 10:299–307

    Article  PubMed  CAS  Google Scholar 

  • Ku SC, Ng DT, Yap MG, Chao SH (2008) Effects of overexpression of X-box binding protein 1 on recombinant protein production in Chinese hamster ovary and NS0 myeloma cells. Biotechnol Bioeng 99:155–164

    Article  PubMed  CAS  Google Scholar 

  • Kwaks TH, Otte AP (2006) Employing epigenetics to augment the expression of therapeutic proteins in mammalian cells. Trends Biotechnol 24:137–142

    Article  PubMed  CAS  Google Scholar 

  • Kwaks TH, Barnett P, Hemrika W, Siersma T, Sewalt RG, Satijn DP, Brons JF, van Blokland R, Kwakman P, Kruckeberg AL, Kelder A, Otte AP (2003) Identification of anti-repressor elements that confer high and stable protein production in mammalian cells. Nat Biotechnol 21:553–558

    Article  PubMed  CAS  Google Scholar 

  • Lee GM, Varma A, Palsson BO (1991) Application of population balance model to the loss of hybridoma antibody productivity. Biotechnol Prog 7:72–75

    Article  PubMed  CAS  Google Scholar 

  • Lee YK, Brewer JW, Hellman R, Hendershot LM (1999) BiP and immunoglobulin light chain cooperate to control the folding of heavy chain and ensure the fidelity of immunoglobulin assembly. Mol Biol Cell 10:2209–2219

    PubMed  CAS  Google Scholar 

  • Leitzgen K, Knittler MR, Haas IG (1997) Assembly of immunoglobulin light chains as a prerequisite for secretion. A model for oligomerization-dependent subunit folding. J Biol Chem 272:3117–3123

    Article  PubMed  CAS  Google Scholar 

  • Leno M, Merten OW, Hache J (1992) Kinetic-analysis of hybridoma growth and monoclonal-antibody production in semicontinuous culture. Biotechnol Bioeng 39:596–606

    Article  PubMed  CAS  Google Scholar 

  • Li CY, Little JB, Hu K, Zhang W, Zhang L, Dewhirst MW, Huang Q (2001) Persistent genetic instability in cancer cells induced by non-DNA-damaging stress exposures. Cancer Res 61:428–432

    PubMed  CAS  Google Scholar 

  • Li H, Sethuraman N, Stadheim TA, Zha D, Prinz B, Ballew N, Bobrowicz P, Choi BK, Cook WJ, Cukan M, Houston-Cummings NR, Davidson R, Gong B, Hamilton SR, Hoopes JP, Jiang Y, Kim N, Mansfield R, Nett JH, Rios S, Strawbridge R, Wildt S, Gerngross TU (2006) Optimization of humanized IgG’s in glycoengineered Pichia pastoris. Nat Biotechnol 24:210–215

    Article  PubMed  CAS  Google Scholar 

  • Li J, Menzel C, Meier D, Zhang C, Dubel S, Jostock T (2007a) A comparative study of different vector designs for the mammalian expression of recombinant IgG antibodies. J Immunol Methods 318:113–124

    Article  PubMed  CAS  Google Scholar 

  • Li J, Zhang C, Jostock T, Dubel S (2007b) Analysis of IgG heavy chain to light chain ratio with mutant Encephalomyocarditis virus internal ribosome entry site. Protein Eng Des Sel 20:491–496

    Article  PubMed  CAS  Google Scholar 

  • Lilie H, McLaughlin S, Freedman R, Buchner J (1994) Influence of protein disulfide-isomerase (Pdi) on antibody folding in-vitro. J Biol Chem 269:14290–14296

    PubMed  CAS  Google Scholar 

  • Ma Y, Hendershot LM (2003) The stressful road to antibody secretion. Nat Immunol 4:310–311

    Article  PubMed  CAS  Google Scholar 

  • Makrides SC (1999) Components of vectors for gene transfer and expression in mammalian cell. Protein Expr Purif 17:183–202

    Article  PubMed  CAS  Google Scholar 

  • Mayer M, Kies U, Kammermeier R, Buchner J (2000) BiP and PDI cooperate in the oxidative folding of antibodies in vitro. J Biol Chem 275:29421–29425

    Article  PubMed  CAS  Google Scholar 

  • McBurney MW, Mai T, Yang X, Jardine K (2002) Evidence for repeat-induced gene silencing in culture Mammalian cells: inactivation of tandem repeats of transfected genes. Exp Cell Res 274:1–8

    Article  PubMed  CAS  Google Scholar 

  • McLean GR, Nakouzi A, Casadevall A, Green NS (2000) Human and murine immunoglobulin expression vector cassettes. Mol Immunol 37:837–845

    Article  PubMed  CAS  Google Scholar 

  • Meier JL, Stinski MF (1996) Regulation of human cytomegalovirus immediate-early gene expression. Intervirology 39:331–342

    PubMed  CAS  Google Scholar 

  • Melnick JH, Dul JL, Argon Y (1994) Sequential interaction of the chaperones BiP and GRP94 with immunoglobulin chains in the endoplasmic reticulum. Nature 370:373–375

    Article  PubMed  CAS  Google Scholar 

  • Merten OW, Moeurs D, Keller H, Leno M, Palfi GE, Cabanie L, Couve E (1994) Modified monoclonal-antibody production kinetics, kappa/gamma mRNA levels, and metabolic-activities in a murine hybridoma selected by continuous culture. Biotechnol Bioeng 44:753–764

    Article  PubMed  CAS  Google Scholar 

  • Meunier L, Usherwood YK, Chung KT, Hendershot LM (2002) A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. Mol Biol Cell 13:4456–4469

    Article  PubMed  CAS  Google Scholar 

  • Mezghrani A, Fassio A, Benham A, Simmen T, Braakman I, Sitia R (2001) Manipulation of oxidative protein folding and PDI redox state in mammalian cells. EMBO J 20:6288–6296

    Article  PubMed  CAS  Google Scholar 

  • Mielke C, Tummler M, Schubeler D, von Hoegen I, Hauser H (2000) Stabilized, long-term expression of heterodimeric proteins from tricistronic mRNA. Gene 254:1–8

    Article  PubMed  CAS  Google Scholar 

  • Mohan C, Park SH, Chung JY, Lee GM (2007) Effect of doxycycline-regulated protein disulfide isomerase expression on the specific productivity of recombinant CHO cells: thrombopoietin and antibody. Biotechnol Bioeng 98:611–615

    Article  PubMed  CAS  Google Scholar 

  • Morris AE, Lee CC, Hodges K, Aldrich TL, Krantz C, Smidt PS, Thomas JN (1997) Expression augmenting sequence elements (EASE) isolated from Chinese hamster ovary cells. In: Carrondo MJT, Griffiths B, Moreira JLP (eds) Animal cell technology. Kluwer Academic, The Netherlands, pp 529–534

    Google Scholar 

  • Oh MK, Scoles DR, Haipek C, Strand AD, Gutmann DH, Olson JM, Pulst SM (2003) Genetic heterogeneity of stably transfected cell lines revealed by expression profiling with oligonucleotide microarrays. J Cell Biochem 90:1068–1078

    Article  PubMed  CAS  Google Scholar 

  • Ohya T, Hayashi T, Kiyama E, Nishii H, Miki H, Kobayashi K, Honda K, Omasa T, Ohtake H (2008) Improved production of recombinant human antithrombin III in Chinese hamster ovary cells by ATF4 overexpression. Biotechnol Bioeng 100:317–324

    Article  PubMed  CAS  Google Scholar 

  • Otte AP, Kwaks TH, van Blokland RJ, Sewalt RG, Verhees J, Klaren VN, Siersma TK, Korse HW, Teunissen NC, Botschuijver S, van Mer C, Man SY (2007) Various expression-augmenting DNA elements benefit from STAR-Select, a novel high stringency selection system for protein expression. Biotechnol Prog 23:801–807

    PubMed  CAS  Google Scholar 

  • Page MJ, Sydenham MA (1991) High-level expression of the humanized monoclonal-antibody campath-1 h in Chinese-hamster ovary cells. Biotechnology 9:64–68

    Article  PubMed  CAS  Google Scholar 

  • Pavlou AK, Belsey MJ (2005) The therapeutic antibodies market to 2008. Eur J Pharm Biopharm 59:389–396

    Article  PubMed  Google Scholar 

  • Pavlou AK, Reichert JM (2004) Recombinant protein therapeutics-success rates, market trends and values to 2010. Nat Biotechnol 22:1513–1519

    Article  PubMed  CAS  Google Scholar 

  • Rees S, Coote J, Stables J, Goodson S, Harris S, Lee MG (1996) Bicistronic vector for the creation of stable mammalian cell lines that predisposes all antibiotic resistant cells to express recombinant protein. Biotechniques 20:102–110

    PubMed  CAS  Google Scholar 

  • Reff ME (1993) High-level production of recombinant immunoglobulins in mammalian cells. Curr Opin Biotechnol 4:573–576

    Article  PubMed  CAS  Google Scholar 

  • Reichert JM, Rosensweig CJ, Faden LB, Dewitz MC (2005) Monoclonal antibody successes in the clinic. Nat Biotechnol 23:1073–1078

    Article  PubMed  CAS  Google Scholar 

  • Running Deer J, Allison DS (2004) High-level expression of proteins in mammalian cells using transcription regulatory sequences from the Chinese hamster EF-1alpha gene. Biotechnol Prog 20:880–889

    Article  PubMed  CAS  Google Scholar 

  • Rutkowski DT, Kaufman RJ (2003) All roads lead to ATF4. Dev Cell 4:442–444

    Article  PubMed  CAS  Google Scholar 

  • Rutkowski DT, Kaufman RJ (2004) A trip to the ER: coping with stress. Trends Cell Biol 14:20–28

    Article  PubMed  CAS  Google Scholar 

  • Ryan MD, King AM, Thomas GP (1991) Cleavage of foot-and-mouth disease virus polyprotein is mediated by residues located within a 19 amino acid sequence. J Gen Virol 72:2727–2732

    Article  PubMed  CAS  Google Scholar 

  • Schlatter S, Stansfield SH, Dinnis DM, Racher AJ, Birch JR, James DC (2005) On the optimal ratio of heavy to light chain genes for efficient recombinant antibody production by CHO cells. Biotechnol Prog 21:122–133

    Article  PubMed  CAS  Google Scholar 

  • Seth G, Philp RJ, Lau A, Jiun KY, Yap M, Hu WS (2007) Molecular portrait of high productivity in recombinant NS0 cells. Biotechnol Bioeng 97:933–951

    Article  PubMed  CAS  Google Scholar 

  • Simmons LC, Reilly D, Klimowski L, Raju TS, Meng G, Sims P, Hong K, Shields RL, Damico LA, Rancatore P, Yansura DG (2002) Expression of full-length immunoglobulins in Escherichia coli: rapid and efficient production of aglycosylated antibodies. J Immunol Methods 263:133–147

    Article  PubMed  CAS  Google Scholar 

  • Sleiman RJ, Gray PP, McCall MN, Codamo J, Sunstrom NA (2008) Accelerated cell line development using two-color fluorescence activated cell sorting to select highly expressing antibody-producing clones. Biotechnol Bioeng 99:578–587

    Article  PubMed  CAS  Google Scholar 

  • Smales CM, Dinnis DM, Stansfield SH, Alete D, Sage EA, Birch JR, Racher AJ, Marshall CT, James DC (2004) Comparative proteomic analysis of GS-NS0 murine myeloma cell lines with varying recombinant monoclonal antibody production rate. Biotechnol Bioeng 88:474–488

    Article  PubMed  CAS  Google Scholar 

  • Stansfield SH, Allen EE, Dinnis DM, Racher AJ, Birch JR, James DC (2007) Dynamic analysis of GS-NS0 cells producing a recombinant monoclonal antibody during fed-batch culture. Biotechnol Bioeng 97:410–424

    Article  PubMed  CAS  Google Scholar 

  • Strutzenberger K, Borth N, Kunert R, Steinfellner W, Katinger H (1999) Changes during subclone development and ageing of human antibody-producing recombinant CHO cells. J Biotechnol 69:215–226

    Article  PubMed  CAS  Google Scholar 

  • Tigges M, Fussenegger M (2006) Xbp1-based engineering of secretory capacity enhances the productivity of Chinese hamster ovary cells. Metab Eng 8:264–272

    Article  CAS  Google Scholar 

  • Trill JJ, Shatzman AR, Ganguly S (1995) Production of monoclonal antibodies in COS and CHO Cells. Curr Opin Biotechnol 6:553–560

    Article  PubMed  CAS  Google Scholar 

  • Tu BP, Weissman JS (2004) Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol 164:341–346

    Article  PubMed  CAS  Google Scholar 

  • Underhill MF, Smales CM, Naylor LH, Birch JR, James DC (2007) Transient gene expression levels from multigene expression vectors. Biotechnol Prog 23:435–443

    Article  PubMed  CAS  Google Scholar 

  • Urlaub G, Chasin LA (1980) Isolation of Chinese hamster cell mutants deficient in dihydrofolate reductase activity. Proc Natl Acad Sci USA 77:4216–4220

    Article  PubMed  CAS  Google Scholar 

  • Urlaub G, Kas E, Carothers AM, Chasin LA (1983) Deletion of the diploid dihydrofolate reductase locus from cultured mammalian cells. Cell 33:405–412

    Article  PubMed  CAS  Google Scholar 

  • Vanhove M, Usherwood YK, Hendershot LM (2001) Unassembled Ig heavy chains do not cycle from BiP in vivo but require light chains to trigger their release. Immunity 15:105–114

    Article  PubMed  CAS  Google Scholar 

  • Walsh G (2003) Biopharmaceutical benchmarks 2003. Nat Biotechnol 21:865–870

    Article  PubMed  CAS  Google Scholar 

  • Walsh G (2006) Biopharmaceutical benchmarks 2006. Nat Biotechnol 24:769–776

    Article  PubMed  CAS  Google Scholar 

  • Whiteley EM, Hsu TA, Betenbaugh MJ (1997) Modeling assembly, aggregation and chaperoning of immunoglobulin g production in insect cells. Biotechnol Bioeng 56:106–116

    Article  PubMed  CAS  Google Scholar 

  • Wiberg FC, Rasmussen SK, Frandsen TP, Rasmussen LK, Tengbjerg K, Coljee VW, Sharon J, Yang CY, Bregenholt S, Nielsen LS, Haurum JS, Tolstrup AB (2006) Production of target-specific recombinant human polyclonal antibodies in mammalian cells. Biotechnol Bioeng 94:396–405

    Article  PubMed  CAS  Google Scholar 

  • Wurm FM (2004) Production of recombinant protein therapeutics in cultivated mammalian cells. Nat Biotechnol 22:1393–1398

    Article  PubMed  CAS  Google Scholar 

  • Wurm FM, Pallavicini MG, Arathoon R (1991) Integration and stability of CHO amplicons containing plasmid sequences. Dev Biol Stand 76:69–82

    Google Scholar 

  • Yang Q, Sarnow P (1997) Location of the internal ribosome entry site in the 5′ non-coding region of the immunoglobulin heavy-chain binding protein (BiP) mRNA: evidence for specific RNA-protein interactions. Nucleic Acids Res 25:2800–2807

    Article  PubMed  CAS  Google Scholar 

  • Yoon SK, Hwang SO, Lee GM (2004) Enhancing effect of low temperature on specific antibody productivity of recombinant Chinese hamster ovary cell: clonal variation. Biotechnol Prog 20:1683–1688

    Article  PubMed  CAS  Google Scholar 

  • Zahn-Zabal M, Kobr M, Girod PA, Imhof M, Chatellard P, de Jesus M, Wurm F, Mermod N (2001) Development of stable cell lines for production or regulated expression using matrix attachment regions. J Biotechnol 87:29–42

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Chemical and Process Engineering, University of Sheffield, Mappin Street, Sheffield, S1 3JD, UK

    Sarah L. Davies & David C. James

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  1. Sarah L. Davies
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  2. David C. James
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Correspondence to David C. James .

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  1. Dept. Chemical & Biochemical, University College, Dublin, Belfield, Dublin 4, Ireland

    Mohamed Al-Rubeai

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Davies, S.L., James, D.C. (2009). Engineering Mammalian Cells for Recombinant Monoclonal Antibody Production. In: Al-Rubeai, M. (eds) Cell Line Development. Cell Engineering, vol 6. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2245-5_8

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