1932

Abstract

Regulatory bodies worldwide consider glycosylation to be a critical quality attribute for immunoglobulin G (IgG) and IgG-like therapeutics. This consideration is due to the importance of posttranslational modifications in determining the efficacy, safety, and pharmacokinetic properties of biologics. Given its critical role in protein therapeutic production, we review glycosylation beginning with an overview of the myriad interactions of glycans with other biological factors. We examine the mechanism and drivers for glycosylation during biotherapeutic production and the several competing factors that impact glycan formation, including the abundance of precursor nucleotide sugars, transporters, glycosidases, glycosyltransferases, and process conditions. We explore the role of these factors with a focus on the analytical approaches used to characterize glycosylation and associated processes, followed by the current state of advanced glycosylation modeling techniques. This combination of disciplines allows for a deeper understanding of glycosylation and will lead to more rational glycan control.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-chembioeng-102419-010001
2020-06-07
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/chembioeng/11/1/annurev-chembioeng-102419-010001.html?itemId=/content/journals/10.1146/annurev-chembioeng-102419-010001&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Sha S, Agarabi C, Brorson K, Lee D-Y, Yoon S 2016. N-glycosylation design and control of therapeutic monoclonal antibodies. Trends Biotechnol 34:P835–46
    [Google Scholar]
  2. 2. 
    Li M-Y, Ebel B, Paris C, Chauchard F, Guedon E, Marc A 2018. Real-time monitoring of antibody glycosylation site occupancy by in situ Raman spectroscopy during bioreactor CHO cell cultures. Biotechnol. Prog. 34:486–93
    [Google Scholar]
  3. 3. 
    Yin B, Gao Y, Chung C-y, Yang S, Blake E et al. 2015. Glycoengineering of Chinese hamster ovary cells for enhanced erythropoietin N-glycan branching and sialylation. Biotechnol. Bioeng. 112:2343–51
    [Google Scholar]
  4. 4. 
    Wang Q, Chung CY, Chough S, Betenbaugh MJ 2018. Antibody glycoengineering strategies in mammalian cells. Biotechnol. Bioeng. 115:1378–93
    [Google Scholar]
  5. 5. 
    Skropeta D. 2009. The effect of individual N-glycans on enzyme activity. Bioorg. Med. Chem. 17:2645–53
    [Google Scholar]
  6. 6. 
    Walsh G. 2018. Biopharmaceutical benchmarks 2018. Nat. Biotechnol. 36:1136–45
    [Google Scholar]
  7. 7. 
    Correia IR. 2010. Stability of IgG isotypes in serum. mAbs 2:221–32
    [Google Scholar]
  8. 8. 
    Vidarsson G, Dekkers G, Rispens T 2014. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. 5:520
    [Google Scholar]
  9. 9. 
    Rudge SR, Nims RW. 2018. ICH topic Q 6 B specifications: test procedures and acceptance criteria for biotechnological/biological products Qual. Guidel., ICH, Eur. Med Agency, London:
  10. 10. 
    Wang LX, Tong X, Li C, Giddens JP, Li T 2019. Glycoengineering of antibodies for modulating functions. Annu. Rev. Biochem. 88:433–59
    [Google Scholar]
  11. 11. 
    Nimmerjahn F, Ravetch JV. 2008. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 8:34–47
    [Google Scholar]
  12. 12. 
    Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P et al. 2002. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene. Blood 99:754–58
    [Google Scholar]
  13. 13. 
    Meknache N, Jonsson F, Laurent J, Guinnepain MT, Daeron M 2009. Human basophils express the glycosylphosphatidylinositol-anchored low-affinity IgG receptor FcγRIIIB (CD16B). J. Immunol. 182:2542–50
    [Google Scholar]
  14. 14. 
    Salmon JE, Millard SS, Brogle NL, Kimberly RP 1995. Fc gamma receptor IIIb enhances Fc gamma receptor IIa function in an oxidant-dependent and allele-sensitive manner. J. Clin. Investig. 95:2877–85
    [Google Scholar]
  15. 15. 
    Clarkson SB, Ory PA. 1988. CD16: developmentally regulated IgG Fc receptors on cultured human monocytes. J. Exp. Med. 167:408–20
    [Google Scholar]
  16. 16. 
    Boyd PN, Lines AC, Patel AK 1995. The effect of the removal of sialic acid, galactose and total carbohydrate on the functional activity of Campath-1H. Mol. Immunol. 32:1311–18
    [Google Scholar]
  17. 17. 
    Raju TS. 2008. Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr. Opin. Immunol. 20:471–78
    [Google Scholar]
  18. 18. 
    Peschke B, Keller CW, Weber P, Quast I, Lunemann JD 2017. Fc-galactosylation of human immunoglobulin gamma isotypes improves C1q binding and enhances complement-dependent cytotoxicity. Front. Immunol. 8:646
    [Google Scholar]
  19. 19. 
    Hodoniczky J, Zheng YZ, James DC 2005. Control of recombinant monoclonal antibody effector functions by Fc N-glycan remodeling in vitro. Biotechnol. Prog. 21:1644–52
    [Google Scholar]
  20. 20. 
    Umaña P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE 1999. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat. Biotechnol. 17:176–80
    [Google Scholar]
  21. 21. 
    Schachter H. 1986. Biosynthetic controls that determine the branching and microheterogeneity of protein-bound oligosaccharides. Biochem. Cell Biol. 64:163–81
    [Google Scholar]
  22. 22. 
    Shields RL, Lai J, Keck R, O'Connell LY, Hong K et al. 2002. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human FcγRIII and antibody-dependent cellular toxicity. J. Biol. Chem. 277:26733–40
    [Google Scholar]
  23. 23. 
    Shinkawa T, Nakamura K, Yamane N, Shoji-Hosaka E, Kanda Y et al. 2003. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J. Biol. Chem. 278:3466–73
    [Google Scholar]
  24. 24. 
    Ferrara C, Stuart F, Sondermann P, Brünker P, Umaña P 2006. The carbohydrate at FcγRIIIa Asn-162: an element required for high affinity binding to non-fucosylated IgG glycoforms. J. Biol. Chem. 281:5032–36
    [Google Scholar]
  25. 25. 
    Ferrara C, Grau S, Jäger C, Sondermann P, Brünker P et al. 2011. Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose. PNAS 108:12669–74
    [Google Scholar]
  26. 26. 
    Kanda Y, Yamada T, Mori K, Okazaki A, Inoue M et al. 2007. Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types. Glycobiology 17:104–18
    [Google Scholar]
  27. 27. 
    Zhou Q, Shankara S, Roy A, Qiu H, Estes S et al. 2008. Development of a simple and rapid method for producing non-fucosylated oligomannose containing antibodies with increased effector function. Biotechnol. Bioeng. 99:652–65
    [Google Scholar]
  28. 28. 
    Yu M, Brown D, Reed C, Chung S, Lutman J et al. 2012. Production, characterization and pharmacokinetic properties of antibodies with N-linked mannose-5 glycans. mAbs 4:475–87
    [Google Scholar]
  29. 29. 
    Houde D, Peng Y, Berkowitz SA, Engen JR 2010. Post-translational modifications differentially affect IgG1 conformation and receptor binding. Mol. Cell. Proteom. 9:1716–28
    [Google Scholar]
  30. 30. 
    Thomann M, Schlothauer T, Dashivets T, Malik S, Avenal C et al. 2015. In vitro glycoengineering of IgG1 and its effect on Fc receptor binding and ADCC activity. PLOS ONE 10:e0134949
    [Google Scholar]
  31. 31. 
    Thomann M, Reckermann K, Reusch D, Prasser J, Tejada ML 2016. Fc-galactosylation modulates antibody-dependent cellular cytotoxicity of therapeutic antibodies. Mol. Immunol. 73:69–75
    [Google Scholar]
  32. 32. 
    Dashivets T, Thomann M, Rueger P, Knaupp A, Buchner J, Schlothauer T 2015. Multi-angle effector function analysis of human monoclonal IgG glycovariants. PLOS ONE 10:e0143520
    [Google Scholar]
  33. 33. 
    Wada R, Matsui M, Kawasaki N 2019. Influence of N-glycosylation on effector functions and thermal stability of glycoengineered IgG1 monoclonal antibody with homogeneous glycoforms. mAbs 11:350–72
    [Google Scholar]
  34. 34. 
    Aoyama M, Hashii N, Tsukimura W, Osumi K, Harazono A et al. 2019. Effects of terminal galactose residues in mannose α1–6 arm of Fc-glycan on the effector functions of therapeutic monoclonal antibodies. mAbs 11:826–36
    [Google Scholar]
  35. 35. 
    Higel F, Seidl A, Sörgel F, Friess W 2016. N-glycosylation heterogeneity and the influence on structure, function and pharmacokinetics of monoclonal antibodies and Fc fusion proteins. Eur. J. Pharm. Biopharm. 100:94–100
    [Google Scholar]
  36. 36. 
    van de Bovenkamp FS, Hafkenscheid L, Rispens T, Rombouts Y 2016. The emerging importance of IgG fab glycosylation in immunity. J. Immunol. 196:1435–41
    [Google Scholar]
  37. 37. 
    Wright A, Tao MH, Kabat EA, Morrison SL 1991. Antibody variable region glycosylation: position effects on antigen binding and carbohydrate structure. EMBO J 10:2717–23
    [Google Scholar]
  38. 38. 
    Wu SJ, Luo J, O'Neil KT, Kang J, Lacy ER et al. 2010. Structure-based engineering of a monoclonal antibody for improved solubility. Protein Eng. Des. Sel. 23:643–51
    [Google Scholar]
  39. 39. 
    Bongers J, Devincentis J, Fu J, Huang P, Kirkley DH et al. 2011. Characterization of glycosylation sites for a recombinant IgG1 monoclonal antibody and a CTLA4-Ig fusion protein by liquid chromatography-mass spectrometry peptide mapping. J. Chromatogr. A 1218:8140–49
    [Google Scholar]
  40. 40. 
    Pennica D, Lam VT, Weber RF, Kohr WJ, Basa LJ et al. 1993. Biochemical characterization of the extracellular domain of the 75-kilodalton tumor necrosis factor receptor. Biochemistry 32:3131–38
    [Google Scholar]
  41. 41. 
    Stefanich EG, Ren S, Danilenko DM, Lim A, Song A et al. 2008. Evidence for an asialoglycoprotein receptor on nonparenchymal cells for O-linked glycoproteins. J. Pharmacol. Exp. Ther. 327:308–15
    [Google Scholar]
  42. 42. 
    Keck R, Nayak N, Lerner L, Raju S, Ma S et al. 2008. Characterization of a complex glycoprotein whose variable metabolic clearance in humans is dependent on terminal N-acetylglucosamine content. Biologicals 36:49–60
    [Google Scholar]
  43. 43. 
    Ashkenazi A, Marsters SA, Capon DJ, Chamow SM, Figari IS et al. 1991. Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin. PNAS 88:10535–39
    [Google Scholar]
  44. 44. 
    Larsen RD, Rajan VP, Ruff MM, Kukowska-Latallo J, Cummings RD, Lowe JB 1989. Isolation of a cDNA encoding a murine UDPgalactose:beta-D-galactosyl- 1,4-N-acetyl-D-glucosaminide alpha-1,3-galactosyltransferase: expression cloning by gene transfer. PNAS 86:8227–31
    [Google Scholar]
  45. 45. 
    Chung CH, Mirakhur B, Chan E, Le QT, Berlin J et al. 2008. Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1,3-galactose. N. Engl. J. Med. 358:1109–17
    [Google Scholar]
  46. 46. 
    Borrebaeck CK, Malmborg AC, Ohlin M 1993. Does endogenous glycosylation prevent the use of mouse monoclonal antibodies as cancer therapeutics. ? Immunol. Today 14:477–79
    [Google Scholar]
  47. 47. 
    Deglon N, Aubert V, Spertini F, Winkel L, Aebischer P 2003. Presence of Gal-α1,3Gal epitope on xenogeneic lines: implications for cellular gene therapy based on the encapsulation technology. Xenotransplantation 10:204–13
    [Google Scholar]
  48. 48. 
    Lammerts van Bueren JJ, Rispens T, Verploegen S, van der Palen-Merkus T, Stapel S et al. 2011. Anti-galactose-α-1,3-galactose IgE from allergic patients does not bind α-galactosylated glycans on intact therapeutic antibody Fc domains. Nat. Biotechnol. 29:574–76
    [Google Scholar]
  49. 49. 
    Qian J, Liu T, Yang L, Daus A, Crowley R, Zhou Q 2007. Structural characterization of N-linked oligosaccharides on monoclonal antibody cetuximab by the combination of orthogonal matrix-assisted laser desorption/ionization hybrid quadrupole-quadrupole time-of-flight tandem mass spectrometry and sequential enzymatic digestion. Anal. Biochem. 364:8–18
    [Google Scholar]
  50. 50. 
    Hokke CH, Bergwerff AA, van Dedem GW, van Oostrum J, Kamerling JP, Vliegenthart JF 1990. Sialylated carbohydrate chains of recombinant human glycoproteins expressed in Chinese hamster ovary cells contain traces of N-glycolylneuraminic acid. FEBS Lett 275:9–14
    [Google Scholar]
  51. 51. 
    Noguchi A, Mukuria CJ, Suzuki E, Naiki M 1996. Failure of human immunoresponse to N-glycolylneuraminic acid epitope contained in recombinant human erythropoietin. Nephron 72:599–603
    [Google Scholar]
  52. 52. 
    Varki A. 2007. Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins. Nature 446:1023–29
    [Google Scholar]
  53. 53. 
    Zhu A, Hurst R. 2002. Anti-N-glycolylneuraminic acid antibodies identified in healthy human serum. Xenotransplantation 9:376–81
    [Google Scholar]
  54. 54. 
    Tangvoranuntakul P, Gagneux P, Diaz S, Bardor M, Varki N et al. 2003. Human uptake and incorporation of an immunogenic nonhuman dietary sialic acid. PNAS 100:12045–50
    [Google Scholar]
  55. 55. 
    Roopenian DC, Akilesh S. 2007. FcRn: The neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7:715–25
    [Google Scholar]
  56. 56. 
    Jefferis R. 2012. Isotype and glycoform selection for antibody therapeutics. Arch. Biochem. Biophys. 526:159–66
    [Google Scholar]
  57. 57. 
    Ashwell G, Harford J. 1982. Carbohydrate-specific receptors of the liver. Annu. Rev. Biochem. 51:531–54
    [Google Scholar]
  58. 58. 
    Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J et al. 2002. Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 295:1898–901
    [Google Scholar]
  59. 59. 
    Goetze AM, Liu YD, Zhang Z, Shah B, Lee E et al. 2011. High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology 21:949–59
    [Google Scholar]
  60. 60. 
    Alessandri L, Ouellette D, Acquah A, Rieser M, Leblond D et al. 2012. Increased serum clearance of oligomannose species present on a human IgG1 molecule. mAbs 4:509–20
    [Google Scholar]
  61. 61. 
    Leabman MK, Meng YG, Kelley RF, DeForge LE, Cowan KJ, Iyer S 2013. Effects of altered FcγR binding on antibody pharmacokinetics in cynomolgus monkeys. mAbs 5:896–903
    [Google Scholar]
  62. 62. 
    Larkin A, Imperiali B. 2011. The expanding horizons of asparagine-linked glycosylation. Biochemistry 50:4411–26
    [Google Scholar]
  63. 63. 
    Aebi M. 2013. N-linked protein glycosylation in the ER. Biochim. Biophys. Acta Mol. Cell Res. 1833:2430–37
    [Google Scholar]
  64. 64. 
    Raymond C, Robotham A, Spearman M, Butler M, Kelly J, Durocher Y 2015. Production of α2,6-sialylated IgG1 in CHO cells. mAbs 7:571–83
    [Google Scholar]
  65. 65. 
    Jones J, Krag SS, Betenbaugh MJ 2005. Controlling N-linked glycan site occupancy. Biochim. Biophys. Acta Gen. Subj. 1726:121–37
    [Google Scholar]
  66. 66. 
    Freeze HH, Hart GW, Schnaar RL 2017. Glycosylation precursors. Essentials of Glycobiology A Varki, RD Cummings, JD Esko, P Stanley, GW Hart et al. chapter 5 New York: Cold Spring Harb. Lab. Press. , 3rd ed..
    [Google Scholar]
  67. 67. 
    Nyberg GB, Balcarcel RR, Follstad BD, Stephanopoulos G, Wang DI 1999. Metabolic effects on recombinant interferon-γ glycosylation in continuous culture of Chinese hamster ovary cells. Biotechnol. Bioeng. 62:336–47
    [Google Scholar]
  68. 68. 
    Burleigh SC, Laar TVD, Stroop CJM, Grunsven WMJV, Donoghue NO et al. 2011. Synergizing metabolic flux analysis and nucleotide sugar metabolism to understand the control of glycosylation of recombinant protein in CHO cells. BMC Biotechnol 11:95
    [Google Scholar]
  69. 69. 
    Slade PG, Caspary RG, Nargund S, Huang CJ 2016. Mannose metabolism in recombinant CHO cells and its effect on IgG glycosylation. Biotechnol. Bioeng. 113:1468–80
    [Google Scholar]
  70. 70. 
    Wong NS, Wati L, Nissom PM, Feng HT, Lee MM, Yap MG 2010. An investigation of intracellular glycosylation activities in CHO cells: effects of nucleotide sugar precursor feeding. Biotechnol. Bioeng. 107:321–36
    [Google Scholar]
  71. 71. 
    Hossler P, Racicot C, Chumsae C, McDermott S, Cochran K 2017. Cell culture media supplementation of infrequently used sugars for the targeted shifting of protein glycosylation profiles. Biotechnol. Prog. 33:511–22
    [Google Scholar]
  72. 72. 
    Bruhlmann D, Muhr A, Parker R, Vuillemin T, Bucsella B et al. 2017. Cell culture media supplemented with raffinose reproducibly enhances high mannose glycan formation. J. Biotechnol. 252:32–42
    [Google Scholar]
  73. 73. 
    Naik HM, Majewska NI, Betenbaugh MJ 2018. Impact of nucleotide sugar metabolism on protein N-glycosylation in Chinese Hamster Ovary (CHO) cell culture. Curr. Opin. Chem. Eng. 22:167–76
    [Google Scholar]
  74. 74. 
    Gerardy-Schahn R, Oelmann S, Bakker H 2001. Nucleotide sugar transporters: biological and functional aspects. Biochimie 83:775–82
    [Google Scholar]
  75. 75. 
    Caffaro CE, Hirschberg CB. 2006. Nucleotide sugar transporters of the Golgi apparatus: from basic science to diseases. Acc. Chem. Res. 39:805–12
    [Google Scholar]
  76. 76. 
    Berninsone P, Hirschberg CB. 2000. Nucleotide sugar transporters of the Golgi apparatus. Curr. Opin. Struct. Biol. 10:542–47
    [Google Scholar]
  77. 77. 
    Wong NS, Yap MG, Wang DI 2006. Enhancing recombinant glycoprotein sialylation through CMP-sialic acid transporter over expression in Chinese hamster ovary cells. Biotechnol. Bioeng. 93:1005–16
    [Google Scholar]
  78. 78. 
    Kainuma M, Chiba Y, Takeuchi M, Jigami Y 2001. Overexpression of HUT1 gene stimulates in vivo galactosylation by enhancing UDP-galactose transport activity in Saccharomyces cerevisiae. . Yeast 18:533–41
    [Google Scholar]
  79. 79. 
    Maszczak-Seneczko D, Olczak T, Jakimowicz P, Olczak M 2011. Overexpression of UDP-GlcNAc transporter partially corrects galactosylation defect caused by UDP-Gal transporter mutation. FEBS Lett 585:3090–94
    [Google Scholar]
  80. 80. 
    Elliott S, Lorenzini T, Asher S, Aoki K, Brankow D et al. 2003. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat. Biotechnol. 21:414–21
    [Google Scholar]
  81. 81. 
    Ruiz-Canada C, Kelleher DJ, Gilmore R 2009. Cotranslational and posttranslational N-glycosylation of polypeptides by distinct mammalian OST isoforms. Cell 136:272–83
    [Google Scholar]
  82. 82. 
    Schulz BL, Stirnimann CU, Grimshaw JPA, Brozzo MS, Fritsch F et al. 2009. Oxidoreductase activity of oligosaccharyltransferase subunits Ost3p and Ost6p defines site-specific glycosylation efficiency. PNAS 106:11061–66
    [Google Scholar]
  83. 83. 
    Jenkins N, Castro P, Menon S, Ison A, Bull A 1994. Effect of lipid supplements on the production and glycosylation of recombinant interferon-γ expressed in CHO cells. Cytotechnology 15:209–15
    [Google Scholar]
  84. 84. 
    Gawlitzek M, Estacio M, Fürch T, Kiss R 2009. Identification of cell culture conditions to control N-glycosylation site-occupancy of recombinant glycoproteins expressed in CHO cells. Biotechnol. Bioeng. 103:1164–75
    [Google Scholar]
  85. 85. 
    Villacrés C, Tayi VS, Lattová E, Perreault H, Butler M 2015. Low glucose depletes glycan precursors, reduces site occupancy and galactosylation of a monoclonal antibody in CHO cell culture. Biotechnol. J. 10:1051–66
    [Google Scholar]
  86. 86. 
    Haeuptle MA, Welti M, Troxler H, Hülsmeier AJ, Imbach T, Hennet T 2011. Improvement of dolichol-linked oligosaccharide biosynthesis by the squalene synthase inhibitor zaragozic acid. J. Biol. Chem. 286:6085–91
    [Google Scholar]
  87. 87. 
    Cosson P, de Curtis I, Pouyssegur J, Griffiths G, Davoust J 1989. Low cytoplasmic pH inhibits endocytosis and transport from the trans-Golgi network to the cell surface. J. Cell Biol. 108:377–87
    [Google Scholar]
  88. 88. 
    Farquhar MG, Palade GE. 1981. The Golgi apparatus (complex)—(1954–1981)—from artifact to center stage. J. Cell Biol. 91:77s–103s
    [Google Scholar]
  89. 89. 
    Xiang Y, Zhang X, Nix DB, Katoh T, Aoki K et al. 2013. Regulation of protein glycosylation and sorting by the Golgi matrix proteins GRASP55/65. Nat. Commun. 4:1659
    [Google Scholar]
  90. 90. 
    Ungar D, Oka T, Krieger M, Hughson FM 2006. Retrograde transport on the COG railway. Trends Cell Biol 16:113–20
    [Google Scholar]
  91. 91. 
    Lees JA, Yip CK, Walz T, Hughson FM 2010. Molecular organization of the COG vesicle tethering complex. Nat. Struct. Mol. Biol. 17:1292–97
    [Google Scholar]
  92. 92. 
    Miller VJ, Ungar D. 2012. Re'COG'nition at the Golgi. Traffic 13:891–97
    [Google Scholar]
  93. 93. 
    Maeda Y, Kinoshita T. 2010. The acidic environment of the Golgi is critical for glycosylation and transport. Methods Enzymol 480:495–510
    [Google Scholar]
  94. 94. 
    Dong Z, Zuber C, Pierce M, Stanley P, Roth J 2014. Reduction in Golgi apparatus dimension in the absence of a residential protein, N-acetylglucosaminyltransferase V. Histochem. Cell Biol. 141:153–64
    [Google Scholar]
  95. 95. 
    Lairson LL, Henrissat B, Davies GJ, Withers SG 2008. Glycosyltransferases: structures, functions, and mechanisms. Annu. Rev. Biochem. 77:521–55
    [Google Scholar]
  96. 96. 
    Rini JM, Esko JD. 2017. Glycosyltransferases and glycan-processing enzymes. Essentials of Glycobiology A Varki, RD Cummings, JD Esko, P Stanley, GW Hart et al. chapter 6 New York: Cold Spring Harb. Lab. Press. , 3rd ed..
    [Google Scholar]
  97. 97. 
    Youakim A, Shur BD. 1994. Alteration of oligosaccharide biosynthesis by genetic manipulation of glycosyltransferases. Ann. N.Y. Acad. Sci. 745:331–35
    [Google Scholar]
  98. 98. 
    Dunphy WG, Rothman JE. 1985. Compartmental organization of the Golgi stack. Cell 42:13–21
    [Google Scholar]
  99. 99. 
    Roth J, Berger EG. 1982. Immunocytochemical localization of galactosyltransferase in HeLa cells: codistribution with thiamine pyrophosphatase in trans-Golgi cisternae. J. Cell Biol. 93:223–29
    [Google Scholar]
  100. 100. 
    Tu L, Banfield DK. 2010. Localization of Golgi-resident glycosyltransferases. Cell. Mol. Life Sci. 67:29–41
    [Google Scholar]
  101. 101. 
    Ahn YH, Kim JY, Yoo JS 2015. Quantitative mass spectrometric analysis of glycoproteins combined with enrichment methods. Mass Spectrom. Rev. 34:148–65
    [Google Scholar]
  102. 102. 
    Ruhaak LR, Zauner G, Huhn C, Bruggink C, Deelder AM, Wuhrer M 2010. Glycan labeling strategies and their use in identification and quantification. Anal. Bioanal. Chem. 397:3457–81
    [Google Scholar]
  103. 103. 
    Goldman R, Sanda M. 2015. Targeted methods for quantitative analysis of protein glycosylation. Proteom. Clin. Appl. 9:17–32
    [Google Scholar]
  104. 104. 
    Schubert M, Walczak MJ, Aebi M, Wider G. 2015. Posttranslational modifications of intact proteins detected by NMR spectroscopy: application to glycosylation. Angew. Chem. Int. Ed. 547096–100
    [Google Scholar]
  105. 105. 
    Creamer JS, Oborny NJ, Lunte SM 2014. Recent advances in the analysis of therapeutic proteins by capillary and microchip electrophoresis. Anal. Methods 6:5427–49
    [Google Scholar]
  106. 106. 
    Zhou S-M, Cheng L, Guo S-J, Zhu H, Tao S-C 2011. Lectin microarrays: a powerful tool for glycan-based biomarker discovery. Comb. Chem. High Throughput Screen. 14:711–19
    [Google Scholar]
  107. 107. 
    Wang W, Soriano B, Chen Q 2017. Glycan profiling of proteins using lectin binding by Surface Plasmon Resonance. Anal. Biochem. 538:53–63
    [Google Scholar]
  108. 108. 
    Cymer F, Beck H, Rohde A, Reusch D 2017. Therapeutic monoclonal antibody N-glycosylation—structure, function and therapeutic potential. Biologicals 52:1–11
    [Google Scholar]
  109. 109. 
    Peter-Katalinić J. 2007. Mass spectrometry and glycomics. . Supramolecular Structure and Function 9 G Pifat-Mrzljak pp. 89–102 Dordrecht, Neth.: Springer
    [Google Scholar]
  110. 110. 
    Yu Q, Wang B, Chen Z, Urabe G, Glover MS et al. 2017. Electron-transfer/higher-energy collision dissociation (EThcD)-enabled intact glycopeptide/glycoproteome characterization. J. Am. Soc. Mass Spectrom. 28:1751–64
    [Google Scholar]
  111. 111. 
    Kozak RP, Tortosa CB, Fernandes DL, Spencer DIR 2015. Comparison of procainamide and 2-aminobenzamide labeling for profiling and identification of glycans liquid chromatography with fluorescence detection coupled to electrospray ionization-mass spectrometry. Anal. Biochem. 486:38–40
    [Google Scholar]
  112. 112. 
    Chokkathukalam A, Kim DH, Barrett MP, Breitling R, Creek DJ 2014. Stable isotope-labeling studies in metabolomics: new insights into structure and dynamics of metabolic networks. Bioanalysis 6:511–24
    [Google Scholar]
  113. 113. 
    Wei L, Cai Y, Yang L, Zhang Y, Lu H 2018. Duplex stable isotope labeling (DuSIL) for simultaneous quantitation and distinction of sialylated and neutral N-glycans by MALDI-MS. Anal. Chem. 90:10442–49
    [Google Scholar]
  114. 114. 
    Pabst M, Benešová I, Fagerer SR, Jacobsen M, Eyer K et al. 2016. Differential isotope labeling of glycopeptides for accurate determination of differences in site-specific glycosylation. J. Proteome Res. 15:326–31
    [Google Scholar]
  115. 115. 
    Orlando R, Lim J-M, Atwood J, Angel PM, Fang M et al. 2008. IDAWG: metabolic incorporation of stable isotope labels for quantitative glycomics of cultured cells research articles. J. Proteome Res. 8:3816–23
    [Google Scholar]
  116. 116. 
    Hennion MC. 2000. Graphitized carbons for solid-phase extraction. J. Chromatogr. A 885:73–95
    [Google Scholar]
  117. 117. 
    Braasch K, Villacres C, Butler M 2015. Evaluation of quenching and extraction methods for nucleotide/nucleotide sugar analysis. Methods Mol. Biol. 1321:361–72
    [Google Scholar]
  118. 118. 
    Tomiya N, Ailor E, Lawrence SM, Betenbaugh MJ, Lee YC 2001. Determination of nucleotides and sugar nucleotides involved in protein glycosylation by high-performance anion-exchange chromatography: sugar nucleotide contents in cultured insect cells and mammalian cells. Anal. Biochem. 293:129–37
    [Google Scholar]
  119. 119. 
    Barnes J, Tian L, Loftis J, Hiznay J, Comhair S et al. 2016. Isolation and analysis of sugar nucleotides using solid phase extraction and fluorophore assisted carbohydrate electrophoresis. MethodsX 3:251–60
    [Google Scholar]
  120. 120. 
    Pabst M, Grass J, Fischl R, Leonard R, Jin C et al. 2010. Nucleotide and nucleotide sugar analysis by liquid chromatography-electrospray ionization-mass spectrometry on surface-conditioned porous graphitic carbon. Anal. Chem. 82:9782–88
    [Google Scholar]
  121. 121. 
    Rejzek M, Hill L, Hems ES, Kuhaudomlarp S, Wagstaff BA, Field RA 2017. Profiling of sugar nucleotides. Methods Enzymol 597:209–38
    [Google Scholar]
  122. 122. 
    Wang C, Wang J, Chen M, Fan L, Zhao L, Tan W-S 2018. Ultra-low carbon dioxide partial pressure improves the galactosylation of a monoclonal antibody produced in Chinese hamster ovary cells in a bioreactor. Biotechnol. Lett. 40:1201–8
    [Google Scholar]
  123. 123. 
    Sou SN, Sellick C, Lee K, Mason A, Kyriakopoulos S et al. 2015. How does mild hypothermia affect monoclonal antibody glycosylation. ? Biotechnol. Bioeng. 112:1165–76
    [Google Scholar]
  124. 124. 
    Shen R, Wang S, Ma X, Xian J, Li J et al. 2010. An easy colorimetric assay for glycosyltransferases. Biochemistry 75:944–50
    [Google Scholar]
  125. 125. 
    Kumagai K, Kojima H, Okabe T, Nagano T 2014. Development of a highly sensitive, high-throughput assay for glycosyltransferases using enzyme-coupled fluorescence detection. Anal. Biochem. 447:146–55
    [Google Scholar]
  126. 126. 
    Losfeld ME, Soncin F, Ng BG, Singec I, Freeze HH 2012. A sensitive green fluorescent protein biomarker of N-glycosylation site occupancy. FASEB J 26:4210–17
    [Google Scholar]
  127. 127. 
    Goldman MH, James DC, Rendall M, Ison AP, Hoare M, Bull AT 1998. Monitoring recombinant human interferon-gamma N-glycosylation during perfused fluidized-bed and stirred-tank batch culture of CHO cells. Biotechnol. Bioeng. 60:596–607
    [Google Scholar]
  128. 128. 
    Paroutis P, Touret N, Grinstein S 2004. The pH of the secretory pathway: measurement, determinants, and regulation. Physiology 19:207–15
    [Google Scholar]
  129. 129. 
    Kim JH, Lingwood CA, Williams DB, Furuya W, Manolson MF, Grinstein S 1996. Dynamic measurement of the pH of the Golgi complex in living cells using retrograde transport of the verotoxin receptor. J. Cell Biol. 134:1387–99
    [Google Scholar]
  130. 130. 
    Demaurex N, Furuya W, D'Souza S, Bonifacino JS, Grinstein S 1998. Mechanism of acidification of the trans-Golgi network (TGN): in situ measurements of pH using retrieval of TGN38 and furin from the cell surface. J. Biol. Chem. 273:2044–51
    [Google Scholar]
  131. 131. 
    Ujvari A, Aron R, Eisenhaure T, Cheng E, Parag HA et al. 2001. Translation rate of human tyrosinase determines its N-linked glycosylation level. J. Biol. Chem. 276:5924–31
    [Google Scholar]
  132. 132. 
    Fierro-Monti I, Racle J, Hernandez C, Waridel P, Hatzimanikatis V, Quadroni M 2013. A novel pulse-chase SILAC strategy measures changes in protein decay and synthesis rates induced by perturbation of proteostasis with an Hsp90 inhibitor. PLOS ONE 8:e80423
    [Google Scholar]
  133. 133. 
    Puri A, Neelamegham S. 2012. Understanding glycomechanics using mathematical modeling: a review of current approaches to simulate cellular glycosylation reaction networks. Ann. Biomed. Eng. 40:816–27
    [Google Scholar]
  134. 134. 
    Umaña P, Bailey JE. 1997. A mathematical model of N-linked glycoform biosynthesis. Biotechnol. Bioeng. 55:890–908
    [Google Scholar]
  135. 135. 
    Antoniewicz MR. 2015. Methods and advances in metabolic flux analysis: a mini-review. J. Ind. Microbiol. Biotechnol. 42:317–25
    [Google Scholar]
  136. 136. 
    Shelikoff M, Sinskey AJ, Stephanopoulos G 1996. A modeling framework for the study of protein glycosylation. Biotechnol. Bioeng. 50:73–90
    [Google Scholar]
  137. 137. 
    Monica TJ, Andersen DC, Goochee CF 1997. A mathematical model of sialylation of N-linked oligosaccharides in the trans-Golgi network. Glycobiology 7:515–21
    [Google Scholar]
  138. 138. 
    Krambeck FJ, Betenbaugh MJ. 2005. A mathematical model of N-linked glycosylation. Biotechnol. Bioeng. 92:711–28
    [Google Scholar]
  139. 139. 
    Krambeck FJ, Bennun SV, Narang S, Choi S, Yarema KJ, Betenbaugh MJ 2009. A mathematical model to derive N-glycan structures and cellular enzyme activities from mass spectrometric data. Glycobiology 19:1163–75
    [Google Scholar]
  140. 140. 
    Hossler P, Mulukutla BC, Hu WS 2007. Systems analysis of N-glycan processing in mammalian cells. PLOS ONE 2:e713
    [Google Scholar]
  141. 141. 
    Kim P-J, Lee D-Y, Jeong H 2009. Centralized modularity of N-linked glycosylation pathways in mammalian cells. PLOS ONE 4:e7317
    [Google Scholar]
  142. 142. 
    Spahn PN, Hansen AH, Hansen HG, Arnsdorf J, Kildegaard HF, Lewis NE 2016. A Markov chain model for N-linked protein glycosylation—towards a low-parameter tool for model-driven glycoengineering. Metab. Eng. 33:52–66
    [Google Scholar]
  143. 143. 
    Kremkow BG, Lee KH. 2018. Glyco-Mapper: a Chinese hamster ovary (CHO) genome-specific glycosylation prediction tool. Metab. Eng. 47:134–42
    [Google Scholar]
  144. 144. 
    del Val IJ, Nagy JM, Kontoravdi C 2011. A dynamic mathematical model for monoclonal antibody N-linked glycosylation and nucleotide sugar donor transport within a maturing Golgi apparatus. Biotechnol. Prog. 27:1730–43
    [Google Scholar]
  145. 145. 
    Villiger TK, Scibona E, Stettler M, Broly H, Morbidelli M, Soos M 2016. Controlling the time evolution of mAb N-linked glycosylation—part II: model-based predictions. Biotechnol. Progress 32:1135–48
    [Google Scholar]
  146. 146. 
    Jedrzejewski P, del Val IJ, Constantinou A, Dell A, Haslam S et al. 2014. Towards controlling the glycoform: a model framework linking extracellular metabolites to antibody glycosylation. Int. J. Mol. Sci. 15:4492–522
    [Google Scholar]
  147. 147. 
    del Val IJ, Polizzi KM, Kontoravdi C 2016. A theoretical estimate for nucleotide sugar demand towards Chinese Hamster Ovary cellular glycosylation. Sci. Rep. 6:28547
    [Google Scholar]
  148. 148. 
    Karst DJ, Scibona E, Serra E, Bielser JM, Souquet J et al. 2017. Modulation and modeling of monoclonal antibody N-linked glycosylation in mammalian cell perfusion reactors. Biotechnol. Bioeng. 114:1978–90
    [Google Scholar]
  149. 149. 
    Sou SN, Jedrzejewski PM, Lee K, Sellick C, Polizzi KM, Kontoravdi C 2017. Model-based investigation of intracellular processes determining antibody Fc-glycosylation under mild hypothermia. Biotechnol. Bioeng. 114:1570–82
    [Google Scholar]
  150. 150. 
    St Amand MM, Hayes J, Radhakrishnan D, Fernandez J, Meyer B et al. 2016. Identifying a robust design space for glycosylation during monoclonal antibody production. Biotechnol. Prog. 32:1149–62
    [Google Scholar]
  151. 151. 
    Kotidis P, Jedrzejewski P, Sou SN, Sellick C, Polizzi K et al. 2019. Model-based optimisation of antibody galactosylation in CHO cell culture. Biotechnol. Bioeng. 116:1612–26
    [Google Scholar]
  152. 152. 
    Dhara VG, Naik HM, Majewska NI, Betenbaugh MJ 2018. Recombinant antibody production in CHO and NS0 cells: differences and similarities. BioDrugs 32:571–84
    [Google Scholar]
  153. 153. 
    Onitsuka M, Kim WD, Ozaki H, Kawaguchi A, Honda K et al. 2012. Enhancement of sialylation on humanized IgG-like bispecific antibody by overexpression of α2,6-sialyltransferase derived from Chinese hamster ovary cells. Appl. Microbiol. Biotechnol. 94:169–80
    [Google Scholar]
  154. 154. 
    Lin N, Mascarenhas J, Sealover NR, George HJ, Brooks J et al. 2015. Chinese hamster ovary (CHO) host cell engineering to increase sialylation of recombinant therapeutic proteins by modulating sialyltransferase expression. Biotechnol. Prog. 31:2334–46
    [Google Scholar]
/content/journals/10.1146/annurev-chembioeng-102419-010001
Loading
/content/journals/10.1146/annurev-chembioeng-102419-010001
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error