Skip to main content
SpringerLink
Log in

Glycosylation of Therapeutic Proteins

An Effective Strategy to Optimize Efficacy

  • Review Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

During their development and administration, protein-based drugs routinely display suboptimal therapeutic efficacies due to their poor physicochemical and pharmacological properties. These innate liabilities have driven the development of molecular strategies to improve the therapeutic behavior of protein drugs. Among the currently developed approaches, glycoengineering is one of the most promising, because it has been shown to simultaneously afford improvements in most of the parameters necessary for optimization of in vivo efficacy while allowing for targeting to the desired site of action. These include increased in vitro and in vivo molecular stability (due to reduced oxidation, cross-linking, pH-, chemical-, heating-, and freezing-induced unfolding/denaturation, precipitation, kinetic inactivation, and aggregation), as well as modulated pharmacodynamic responses (due to altered potencies from diminished in vitro enzymatic activities and altered receptor binding affinities) and improved pharmacokinetic profiles (due to altered absorption and distribution behaviors, longer circulation lifetimes, and decreased clearance rates). This article provides an account of the effects that glycosylation has on the therapeutic efficacy of protein drugs and describes the current understanding of the mechanisms by which glycosylation leads to such effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I

Similar content being viewed by others

References

  1. Andersen DC, Krummen L. Recombinant protein expression for therapeutic applications. Curr Opin Biotechnol 2002; 13(2): 117–23

    Article  PubMed  CAS  Google Scholar 

  2. Carpenter JF, Manning MC, Randolph TW. Long-term storage of proteins. Curr Protoc Protein Sci 2002; Suppl. 27: 4.6. 1–4.6.6

    Google Scholar 

  3. Hawe A, Friess W. Formulation development for hydrophobic therapeutic proteins. Pharm Dev Technol 2007; 12(3): 223–37

    Article  PubMed  CAS  Google Scholar 

  4. Wang W. Instability, stabilization, and formulation of liquid protein pharmaceuticals. Int J Pharm 1999; 185(2): 129–88

    Article  PubMed  CAS  Google Scholar 

  5. Frokjaer S, Otzen DE. Protein drug stability: a formulation challenge. Nature Rev Drug Discov 2005; 4(4): 298–306

    Article  CAS  Google Scholar 

  6. Manning MC, Patel K, Borchardt RT. Stability of protein pharmaceuticals. Pharm Res 1989; 6(11): 903–18

    Article  PubMed  CAS  Google Scholar 

  7. Davis GC. Protein stability: impact upon protein pharmaceuticals [letter]. Biologicals 1993; 21(2): 105

    Article  PubMed  CAS  Google Scholar 

  8. Krishnamurthy R, Manning MC. The stability factor: importance in formulation development. Curr Pharm Biotechnol 2002; 3(4): 361–71

    Article  PubMed  CAS  Google Scholar 

  9. Arakawa T, Prestrelski SJ, Kenney WC, et al. Factors affecting short-term and long-term stabilities of proteins. Adv Drug Deliv Rev 2001; 46(1-3): 307–26

    Article  PubMed  CAS  Google Scholar 

  10. Lee JC. Biopharmaceutical formulation. Curr Opin Biotechnol 2000; 11(1): 81–4

    Article  PubMed  CAS  Google Scholar 

  11. Wang W. Protein aggregation and its inhibition in biopharmaceutics. Int J Pharm 2005; 289(1-2): 1–30

    Article  PubMed  CAS  Google Scholar 

  12. Patro SY, Freund E, Chang BS. Protein formulation and fill-finish operations. Biotechnol Annu Rev 2002; 8: 55–84

    Article  PubMed  CAS  Google Scholar 

  13. Sola RJ, Griebenow K. Effects of glycosylation on the stability of protein pharmaceuticals. J Pharm Sci 2009; 98(4): 1223–45

    Article  PubMed  CAS  Google Scholar 

  14. Brown LR. Commercial challenges of protein drug delivery. Expert Opin Drug Deliv 2005; 2(1): 29–42

    Article  PubMed  Google Scholar 

  15. Mahmood I, Green MD. Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins. Clin Pharmacokinet 2005; 44(4): 331–47

    Article  PubMed  CAS  Google Scholar 

  16. Tang L, Persky AM, Hochhaus G, et al. Pharmacokinetic aspects of biotechnology products. J Pharm Sci 2004; 93(9): 2184–204

    Article  PubMed  CAS  Google Scholar 

  17. Beals JM, Shanafelt AB. Enhancing exposure of protein therapeutics. Drug Discov Today Technol 2006; 3(1): 87–94

    Article  Google Scholar 

  18. Marshall SA, Lazar GA, Chirino AJ, et al. Rational design and engineering of therapeutic proteins. Drug Discov Today 2003; 8(5): 212–21

    Article  PubMed  CAS  Google Scholar 

  19. Lazar GA, Marshall SA, Plecs JJ, et al. Designing proteins for therapeutic applications. Curr Opin Struct Biol 2003; 13(4): 513–8

    Article  PubMed  CAS  Google Scholar 

  20. Jefferis R. Glycosylation of recombinant antibody therapeutics. Biotechnol Prog 2005; 21(1): 11–6

    Article  PubMed  CAS  Google Scholar 

  21. Jefferis R. Glycosylation as a strategy to improve antibody-based therapeutics. Nat Rev Drug Discov 2009; 8(3): 226–34

    Article  PubMed  CAS  Google Scholar 

  22. Jefferis R. Glycosylation of antibody therapeutics: optimization for purpose. Methods Mol Biol 2009; 483: 223–38

    Article  PubMed  CAS  Google Scholar 

  23. Byrne B, Donohoe GG, O’Kennedy R. Sialic acids: carbohydrate moieties that influence the biological and physical properties of biopharmaceutical proteins and living cells. Drug Discov Today 2007; 12(7-8): 319

    Article  PubMed  CAS  Google Scholar 

  24. Sinclair AM, Elliott S. Glycoengineering: the effect of glycosylation on the properties of therapeutic proteins. J Pharm Sci 2005; 94(8): 1626–35

    Article  PubMed  CAS  Google Scholar 

  25. Elliott S, Lorenzini T, Asher S, et al. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat Biotechnol 2003; 21(4): 414–21

    Article  PubMed  CAS  Google Scholar 

  26. Ceaglio N, Etcheverrigaray M, Kratje R, et al. Novel long-lasting interferon alpha derivatives designed by glycoengineering. Biochimie 2008; 90(3): 437–49

    Article  PubMed  CAS  Google Scholar 

  27. Koury MJ. Sugar coating extends half-lives and improves effectiveness of cytokine hormones. Trends Biotechnol 2003; 21(11): 462–4

    Article  PubMed  CAS  Google Scholar 

  28. Raju TS, Briggs JB, Chamow SM, et al. Glycoengineering of therapeutic glycoproteins: in vitro galactosylation and sialylation of glycoproteins with terminal N-acetylglucosamine and galactose residues. Biochemistry 2001; 40(30): 8868–76

    Article  PubMed  CAS  Google Scholar 

  29. Beck A, Wagner-Rousset E, Bussat MC, et al. Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr Pharm Biotechnol 2008; 9(6): 482–501

    Article  PubMed  CAS  Google Scholar 

  30. Wang W. Lyophilization and development of solid protein pharmaceuticals. Int J Pharm 2000; 203(1-2): 1–60

    Article  PubMed  CAS  Google Scholar 

  31. Wang W, Singh S, Zeng DL, et al. Antibody structure, instability, and formulation. J Pharm Sci 2007; 96(1): 1–26

    Article  PubMed  CAS  Google Scholar 

  32. Volkin DB, Mach H, Middaugh CR. Degradative covalent reactions important to protein stability. Mol Biotechnol 1997; 8(2): 105–22

    Article  PubMed  CAS  Google Scholar 

  33. Pace CN. Conformational stability of globular proteins. Trends Biochem Sci 1990; 15(1): 14–7

    Article  PubMed  CAS  Google Scholar 

  34. Xie M, Schowen RL. Secondary structure and protein deamidation. J Pharm Sci 1999; 88(1): 8–13

    Article  PubMed  CAS  Google Scholar 

  35. Pace CN. Measuring and increasing protein stability. Trends Biotechnol 1990; 8(4): 93–8

    Article  PubMed  CAS  Google Scholar 

  36. Valente JJ, Payne RW, Manning MC, et al. Colloidal behavior of proteins: effects of the second virial coefficient on solubility, crystallization and aggregation of proteins in aqueous solution. Curr Pharm Biotechnol 2005; 6(6): 427–36

    Article  PubMed  CAS  Google Scholar 

  37. Chi EY, Krishnan S, Kendrick BS, et al. Roles of conformational stability and colloidal stability in the aggregation of recombinant human granulocyte colony-stimulating factor. Protein Sci 2003; 12(5): 903–13

    Article  PubMed  CAS  Google Scholar 

  38. Kueltzo LA, Wang W, Randolph TW, et al. Effects of solution conditions, processing parameters, and container materials on aggregation of a monoclonal antibody during freeze-thawing. J Pharm Sci 2008; 97(5): 1801–12

    Article  PubMed  CAS  Google Scholar 

  39. Cromwell ME, Hilario E, Jacobson F. Protein aggregation and bioprocessing. AAPS J 2006; 8(3): E572–9

    Article  PubMed  CAS  Google Scholar 

  40. Roberts CJ. Non-native protein aggregation kinetics. Biotechnol Bioeng 2007; 98(5): 927–38

    Article  PubMed  CAS  Google Scholar 

  41. Strober W, Waldmann TA. The role of the kidney in the metabolism of plasma proteins. Nephron 1974; 13(1): 35–66

    Article  PubMed  CAS  Google Scholar 

  42. Caliceti P, Veronese FM. Pharmacokinetic and biodistribution properties of poly (ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 2003; 55(10): 1261–77

    Article  PubMed  CAS  Google Scholar 

  43. Weinstein T, Gafter U, Chagnac A, et al. Distribution of glycosaminoglycans in rat renal tubular epithelium. J Am Soc Nephrol 1997; 8(4): 586–95

    PubMed  CAS  Google Scholar 

  44. Choi HS, Liu W, Misra P, et al. Renal clearance of quantum dots. Nat Biotechnol 2007; 25(10): 1165–70

    Article  PubMed  CAS  Google Scholar 

  45. Montastruc JL, Galitzky J, Berlan M, et al. Mechanism of receptor regulation during repeated administration of drugs. Therapie 1993; 48(5): 421–6

    PubMed  CAS  Google Scholar 

  46. Laduron PM. From receptor internalization to nuclear translocation: new targets for long-term pharmacology. Biochem Pharmacol 1994; 47(1): 3–13

    Article  PubMed  CAS  Google Scholar 

  47. Walsh G. Second-generation biopharmaceuticals. Eur J Pharm Biopharm 2004; 58(2): 185–96

    Article  PubMed  CAS  Google Scholar 

  48. Grabenhorst E, Schlenke P, Pohl S, et al. Genetic engineering of recombinant glycoproteins and the glycosylation pathway in mammalian host cells. Glycoconj J 1999; 16(2): 81–97

    Article  PubMed  CAS  Google Scholar 

  49. Sola RJ, Rodriguez-Martinez JA, Griebenow K. Modulation of protein biophysical properties by chemical glycosylation: biochemical insights and biomedical implications. Cell Mol Life Sci 2007; 64(16): 2133–52

    Article  PubMed  CAS  Google Scholar 

  50. Liu DT. Glycoprotein pharmaceuticals: scientific and regulatory considerations, and the US Orphan Drug Act. Trends Biotechnol 1992; 10(4): 114–20

    Article  PubMed  CAS  Google Scholar 

  51. Weerapana E, Imperiali B. Asparagine-linked protein glycosylation: from eukaryotic to prokaryotic systems. Glycobiology 2006; 16(6): 91–101R

    Article  CAS  Google Scholar 

  52. Mann M, Jensen ON. Proteomic analysis of post-translational modifications. Nature Biotechnol 2003; 21(3): 255–61

    Article  CAS  Google Scholar 

  53. Walsh CT, Garneau-Tsodikova S, Gatto GJ. Protein posttranslational modifications: the chemistry of proteome diversifications. Angewandte Chemie Int Ed 2005; 44(45): 7342–72

    Article  CAS  Google Scholar 

  54. Apweiler R, Hermjakob H, Sharon N. On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta 1999; 1473(1): 4–8

    Article  PubMed  CAS  Google Scholar 

  55. Sears P, Wong CH. Enzyme action in glycoprotein synthesis. Cell Mol Life Sci 1998; 54(3): 223–52

    Article  PubMed  CAS  Google Scholar 

  56. Lehle L, Strahl S, Tanner W. Protein glycosylation, conserved from yeast to man: a model organism helps elucidate congenital human diseases. Angew Chem Int Ed Engl 2006; 45(41): 6802–18

    Article  PubMed  CAS  Google Scholar 

  57. Medzihradszky KF. Characterization of protein N-glycosylation. Methods Enzymol 2005; 405: 116–38

    Article  PubMed  CAS  Google Scholar 

  58. Peter-Katalinic J. Methods in enzymology: O-glycosylation of proteins. Methods Enzymol 2005; 405: 139–71

    Article  PubMed  CAS  Google Scholar 

  59. Hossler P, Mulukutla BC, Hu WS. Systems analysis of N-glycan processing in mammalian cells. PLoS One 2007; 2(1): e713

    Article  PubMed  CAS  Google Scholar 

  60. Sethuraman N, Stadheim TA. Challenges in therapeutic glycoprotein production. Curr Opin Biotechnol 2006; 17(4): 341–6

    Article  PubMed  CAS  Google Scholar 

  61. Hsieh-Wilson LC. Tailor-made glycoproteins. Trends Biotechnol 2004; 22(10): 489–91

    Article  PubMed  CAS  Google Scholar 

  62. Rich JR, Withers SG. Emerging methods for the production of homogeneous human glycoproteins. Nat Chem Biol 2009; 5(4): 206–15

    Article  PubMed  CAS  Google Scholar 

  63. Tarp MA, Clausen H. Mucin-type O-glycosylation and its potential use in drug and vaccine development. Biochim Biophys Acta 2008; 1780(3): 546–63

    Article  PubMed  CAS  Google Scholar 

  64. Brik A, Ficht S, Wong CH. Strategies for the preparation of homogenous glycoproteins. Curr Opin Chem Biol 2006; 10(6): 638–44

    Article  PubMed  CAS  Google Scholar 

  65. Grogan MJ, Pratt MR, Marcaurelle LA, et al. Homogeneous glycopeptides and glycoproteins for biological investigation. Annu Rev Biochem 2002; 71: 593–634

    Article  PubMed  CAS  Google Scholar 

  66. Gamblin DP, Scanlan EM, Davis BG. Glycoprotein synthesis: an update. Chem Rev 2009; 109(1): 131–63

    Article  PubMed  CAS  Google Scholar 

  67. vanKasteren SI, Kramer HB, Gamblin DP, et al. Site-selective glycosylation of proteins: creating synthetic glycoproteins. Nat Protoc 2007; 2(12): 3185–94

    Article  PubMed  CAS  Google Scholar 

  68. Geng J, Mantovani G, Tao L, et al. Site-directed conjugation of ’clicked’ glycopolymers to form glycoprotein mimics: binding to mammalian lectin and induction of immunological function. J Am Chem Soc 2007; 129(49): 15156–63

    Article  PubMed  CAS  Google Scholar 

  69. Vazquez-Dorbatt V, Maynard HD. Biotinylated glycopolymers synthesized by atom transfer radical polymerization. Biomacromolecules 2006; 7(8): 2297–302

    Article  PubMed  CAS  Google Scholar 

  70. Vazquez-Dorbatt V, Tolstyka ZP, Chang CW, et al. Synthesis of a pyridyl disulfide end-functionalized glycopolymer for conjugation to biomolecules and patterning on gold surfaces. Biomacromolecules 2009; 10(8): 2207–12

    Article  PubMed  CAS  Google Scholar 

  71. Choi BK, Bobrowicz P, Davidson RC, et al. Use of combinatorial genetic libraries to humanize N-linked glycosylation in the yeast Pichia pastoris. Proc Natl Acad Sci U S A 2003; 100(9): 5022–7

    Article  PubMed  CAS  Google Scholar 

  72. Li H, Sethuraman N, Stadheim TA, et al. Optimization of humanized IgGs in glycoengineered Pichia pastoris. Nat Biotechnol 2006; 24(2): 210–5

    Article  PubMed  CAS  Google Scholar 

  73. Hamilton SR, Bobrowicz P, Bobrowicz B, et al. Production of complex human glycoproteins in yeast. Science 2003; 301(5637): 1244–6

    Article  PubMed  CAS  Google Scholar 

  74. Hamilton SR, Davidson RC, Sethuraman N, et al. Humanization of yeast to produce complex terminally sialylated glycoproteins. Science 2006; 313(5792): 1441–3

    Article  PubMed  CAS  Google Scholar 

  75. Potgieter TI, Cukan M, Drummond JE, et al. Production of monoclonal antibodies by glycoengineered Pichia pastoris. J Biotechnol 2009; 139(4): 318–25

    Article  PubMed  CAS  Google Scholar 

  76. Chiba Y, Jigami Y. Production of humanized glycoproteins in bacteria and yeasts. Curr Opin Chem Biol 2007; 11(6): 670–6

    Article  PubMed  CAS  Google Scholar 

  77. Karg SR, Kallio PT. The production of biopharmaceuticals in plant systems. Biotechnol Adv 2009; 27(6): 879–94

    Article  PubMed  CAS  Google Scholar 

  78. Hossler P, Khattak SF, Li ZJ. Optimal and consistent protein glycosylation in mammalian cell culture. Glycobiology 2009; 19(9): 936–49

    Article  PubMed  CAS  Google Scholar 

  79. Chiba Y, Akeboshi H. Glycan engineering and production of ‘humanized’ glycoprotein in yeast cells. Biol Pharm Bull 2009; 32(5): 786–95

    Article  PubMed  CAS  Google Scholar 

  80. Ballew N, Gerngross T. Production of therapeutic proteins in fungal hosts. Expert Opin Biol Ther 2004; 4(5): 623–6

    Article  PubMed  CAS  Google Scholar 

  81. Gerngross TU. Advances in the production of human therapeutic proteins in yeasts and filamentous fungi. Nat Biotechnol 2004; 22(11): 1409–14

    Article  PubMed  CAS  Google Scholar 

  82. Bork K, Horstkorte R, Weidemann W. Increasing the sialylation of therapeutic glycoproteins: the potential of the sialic acid biosynthetic pathway. J Pharm Sci 2009; 98(10): 3499–508

    Article  PubMed  CAS  Google Scholar 

  83. Werner RG, Kopp K, Schlueter M. Glycosylation of therapeutic proteins in different production systems. Acta Paediatr Suppl 2007; 96(455): 17–22

    Article  Google Scholar 

  84. Langdon RH, Cuccui J, Wren BW. N-linked glycosylation in bacteria: an unexpected application. Future Microbiol 2009; 4(4): 401–12

    Article  PubMed  CAS  Google Scholar 

  85. Ko K, Ahn MH, Song M, et al. Glyco-engineering of biotherapeutic proteins in plants. Mol Cells 2008; 25(4): 494–503

    PubMed  CAS  Google Scholar 

  86. Mohan C, Kim YG, Koo J, et al. Assessment of cell engineering strategies for improved therapeutic protein production in CHO cells. Biotechnol J 2008; 3(5): 624–30

    Article  PubMed  CAS  Google Scholar 

  87. Shi X, Jarvis DL. Protein N-glycosylation in the baculovirus-insect cell system. Curr Drug Targets 2007; 8(10): 1116–25

    Article  PubMed  CAS  Google Scholar 

  88. Hamilton SR, Gerngross TU. Glycosylation engineering in yeast: the advent of fully humanized yeast. Curr Opin Biotechnol 2007; 18(5): 387–92

    Article  PubMed  CAS  Google Scholar 

  89. Ioannou YA, Zeidner KM, Grace ME, et al. Human alpha-galactosidase A: glycosylation site 3 is essential for enzyme solubility. Biochem J 1998; 332 (Pt 3): 789–97

    PubMed  CAS  Google Scholar 

  90. Clark SE, Muslin EH, Henson CA. Effect of adding and removing N-glycosylation recognition sites on the thermostability of barley alpha-glucosidase. Protein Eng Des Sel 2004; 17(3): 245–9

    Article  PubMed  CAS  Google Scholar 

  91. Kwon KS, Yu MH. Effect of glycosylation on the stability of alpha1-antitrypsin toward urea denaturation and thermal deactivation. Biochim Biophys Acta 1997; 1335(3): 265–72

    Article  PubMed  CAS  Google Scholar 

  92. Sundaram PV, Venkatesh R. Retardation of thermal and urea induced inactivation of alpha-chymotrypsin by modification with carbohydrate polymers. Protein Eng 1998; 11(8): 699–705

    Article  PubMed  CAS  Google Scholar 

  93. Sola RJ, Al-Azzam W, Griebenow K. Engineering of protein thermodynamic, kinetic, and colloidal stability: chemical glycosylation with mono-functionally activated glycans. Biotechnol Bioeng 2006; 94(6): 1072–9

    Article  PubMed  CAS  Google Scholar 

  94. vanZuylen CW, deBeer T, Leeflang BR, et al. Mobilities of the inner three core residues and the Man (alpha 1–6) branch of the glycan at Asn78 of the alpha-subunit of human chorionic gonadotropin are restricted by the protein. Biochemistry 1998; 37(7): 1933–40

    Article  PubMed  Google Scholar 

  95. Uchida E, Morimoto K, Kawasaki N, et al. Effect of active oxygen radicals on protein and carbohydrate moieties of recombinant human erythropoietin. Free Radic Res 1997; 27(3): 311–23

    Article  PubMed  CAS  Google Scholar 

  96. Narhi LO, Arakawa T, Aoki KH, et al. The effect of carbohydrate on the structure and stability of erythropoietin. J Biol Chem 1991; 266(34): 23022–6

    PubMed  CAS  Google Scholar 

  97. Tsuda E, Kawanishi G, Ueda M, et al. The role of carbohydrate in recombinant human erythropoietin. Eur J Biochem 1990; 188(2): 405–11

    Article  PubMed  CAS  Google Scholar 

  98. Runkel L, Meier W, Pepinsky RB, et al. Structural and functional differences between glycosylated and non-glycosylated forms of human interferon-beta (IFN-beta). Pharm Res 1998; 15(4): 641–9

    Article  PubMed  CAS  Google Scholar 

  99. Karpusas M, Whitty A, Runkel L, et al. The structure of human interferonbeta: implications for activity. Cell Mol Life Sci 1998; 54(11): 1203–16

    Article  PubMed  CAS  Google Scholar 

  100. Conradt HS, Egge H, Peter-Katalinic J, et al. Structure of the carbohydrate moiety of human interferon-beta secreted by a recombinant Chinese hamster ovary cell line. J Biol Chem 1987; 262(30): 14600–5

    PubMed  CAS  Google Scholar 

  101. Rudd PM, Joao HC, Coghill E, et al. Glycoforms modify the dynamic stability and functional activity of an enzyme. Biochemistry 1994; 33(1): 17–22

    Article  PubMed  CAS  Google Scholar 

  102. Kim BM, Kim H, Raines RT, et al. Glycosylation of onconase increases its conformational stability and toxicity for cancer cells. Biochem Biophys Res Commun 2004; 315(4): 976–83

    Article  PubMed  CAS  Google Scholar 

  103. Nissen C. Glycosylation of recombinant human granulocyte colony stimulating factor: implications for stability and potency. Eur J Cancer 1994; 30A Suppl. 3: S12–4

    Google Scholar 

  104. Oh-eda M, Hasegawa M, Hattori K, et al. O-linked sugar chain of human granulocyte colony-stimulating factor protects it against polymerization and denaturation allowing it to retain its biological activity. J Biol Chem 1990; 265(20): 11432–5

    PubMed  CAS  Google Scholar 

  105. Ono M. Physicochemical and biochemical characteristics of glycosylated recombinant human granulocyte colony stimulating factor (lenograstim). Eur J Cancer 1994; 30A Suppl. 3: S7–11

    Google Scholar 

  106. Weintraub BD, Stannard BS, Meyers L. Glycosylation of thyroid-stimulating hormone in pituitary tumor cells: influence of high mannose oligosaccharide units on subunit aggregation, combination, and intracellular degradation. Endocrinology 1983; 112(4): 1331–45

    Article  PubMed  CAS  Google Scholar 

  107. Yang B, Li TD. Effect of glycosylation at Asn302 of pro-urokinase on its stability in culture supernatant. Chin Med Sci J 2006; 21(2): 128–30

    PubMed  CAS  Google Scholar 

  108. Baudys M, Uchio T, Mix D, et al. Physical stabilization of insulin by glycosylation. J Pharm Sci 1995; 84(1): 28–33

    Article  PubMed  CAS  Google Scholar 

  109. Liu H, Bulseco GG, Sun J. Effect of posttranslational modifications on the thermal stability of a recombinant monoclonal antibody. Immunol Lett 2006; 106(2): 144–53

    Article  PubMed  CAS  Google Scholar 

  110. Ghirlando R, Lund J, Goodall M, et al. Glycosylation of human IgG-Fc: influences on structure revealed by differential scanning micro-calorimetry. Immunol Lett 1999; 68(1): 47–52

    Article  PubMed  CAS  Google Scholar 

  111. Lis H, Sharon N. Protein glycosylation. Structural and functional aspects. Eur J Biochem 1993; 218(1): 1–27

    Article  PubMed  CAS  Google Scholar 

  112. Varki A. Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 1993; 3(2): 97–130

    Article  PubMed  CAS  Google Scholar 

  113. Vegarud G, Christensen TB. The resistance of glycoproteins to proteolytic inactivation. Acta Chem Scand B 1975; 29(8): 887–8

    Article  PubMed  CAS  Google Scholar 

  114. Vegarud G, Christnsen TB. Glycosylation of proteins: a new method of enzyme stabilization. Biotechnol Bioeng 1975; 17(9): 1391–7

    Article  PubMed  CAS  Google Scholar 

  115. Ueda T, Tomita K, Notsu Y, et al. Chemoenzymatic synthesis of glycosylated glucagon-like peptide 1: effect of glycosylation on proteolytic resistance and in vivo blood glucose-lowering activity. J Am Chem Soc 2009; 131(17): 6237–45

    Article  PubMed  CAS  Google Scholar 

  116. Carter CR, Keeble JR, Thorpe R. Human serum inactivates non-glycosylated but not glycosylated granulocyte colony stimulating factor by a protease dependent mechanism: significance of carbohydrates on the glycosylated molecule. Biologicals 2004; 32(1): 37–47

    Article  PubMed  CAS  Google Scholar 

  117. Wicker-Planquart C, Canaan S, Riviere M, et al. Site-directed removal of N-glycosylation sites in human gastric lipase. Eur J Biochem 1999; 262(3): 644–51

    Article  PubMed  CAS  Google Scholar 

  118. Grinnell BW, Walls JD, Gerlitz B. Glycosylation of human protein C affects its secretion, processing, functional activities, and activation by thrombin. J Biol Chem 1991; 266(15): 9778–85

    PubMed  CAS  Google Scholar 

  119. Wang P, Zhang J, Sun Z, et al. Glycosylation of prourokinase produced by Pichia pastoris impairs enzymatic activity but not secretion. Protein Expr Purif 2000;20(2): 179–85

    Article  PubMed  CAS  Google Scholar 

  120. Sareneva T, Cantell K, Pyhala L, et al. Effect of carbohydrates on the pharmacokinetics of human interferon-gamma. J Interferon Res 1993; 13(4): 267–9

    Article  PubMed  CAS  Google Scholar 

  121. Raju TS, Scallon B. Fc glycans terminated with N-acetylglucosamine residues increase antibody resistance to papain. Biotechnol Prog 2007; 23(4): 964–71

    PubMed  CAS  Google Scholar 

  122. Clowers BH, Dodds ED, Seipert RR, et al. Site determination of protein glycosylation based on digestion with immobilized nonspecific proteases and Fourier transform ion cyclotron resonance mass spectrometry. J Proteome Res 2007; 6(10): 4032–40

    Article  PubMed  CAS  Google Scholar 

  123. Ashwell G, Morell A. The dual role of sialic acid in the hepatic recognition and catabolism of serum glycoproteins. Biochem Soc Symp 1974; (40): 117–24

    PubMed  CAS  Google Scholar 

  124. Ashwell G, Morell AG. The role of surface carbohydrates in the hepatic recognition and transport of circulating glycoproteins. Adv Enzymol Relat Areas Mol Biol 1974; 41(0): 99–128

    PubMed  CAS  Google Scholar 

  125. Stockert RJ, Morell AG, Ashwell G. Structural characteristics and regulation of the asialoglycoprotein receptor. Targeted Diagn Ther 1991; 4: 41–64

    PubMed  CAS  Google Scholar 

  126. Pricer Jr WE, Hudgin RL, Ashwell G, et al. A membrane receptor protein for asialoglycoproteins. Methods Enzymol 1974; 34: 688–91

    Article  PubMed  CAS  Google Scholar 

  127. Morell AG, Irvine RA, Sternlieb I, et al. Physical and chemical studies on ceruloplasmin, V: metabolic studies on sialic acid-free ceruloplasmin in vivo. J Biol Chem 1968; 243(1): 155–9

    PubMed  CAS  Google Scholar 

  128. Gross V, Heinrich PC, vonBerg D, et al. Involvement of various organs in the initial plasma clearance of differently glycosylated rat liver secretory proteins. Eur J Biochem 1988; 173(3): 653–9

    Article  PubMed  CAS  Google Scholar 

  129. Morell AG, Gregoriadis G, Scheinberg IH, et al. The role of sialic acid in determining the survival of glycoproteins in the circulation. J Biol Chem 1971; 246(5): 1461–7

    PubMed  CAS  Google Scholar 

  130. Baynes JW, Wold F. Effect of glycosylation on the in vivo circulating half-life of ribonuclease. J Biol Chem 1976; 251(19): 6016–24

    PubMed  CAS  Google Scholar 

  131. Wileman T, Harding C, Stahl P. Receptor-mediated endocytosis. Biochem J 1985; 232(1): 1–14

    PubMed  CAS  Google Scholar 

  132. Schlesinger PH, Doebber TW, Mandell BF, et al. Plasma clearance of glycoproteins with terminal mannose and N-acetylglucosamine by liver non-parenchymal cells: studies with beta-glucuronidase, N-acetyl-beta-D-glu-cosaminidase, ribonuclease B and agalacto-orosomucoid. Biochem J 1978; 176(1): 103–9

    PubMed  CAS  Google Scholar 

  133. Schlesinger PH, Rodman JS, Doebber TW, et al. The role of extra-hepatic tissues in the receptor-mediated plasma clearance of glycoproteins terminated by mannose or N-acetylglucosamine. Biochem J 1980; 192(2): 597–606

    PubMed  CAS  Google Scholar 

  134. Townsend R, Stahl P. Isolation and characterization of a mannose/N-acetylglucosamine/fucose-binding protein from rat liver. Biochem J 1981; 194(1): 209–14

    PubMed  CAS  Google Scholar 

  135. Achord DT, Brot FE, Bell CE, et al. Human beta-glucuronidase: in vivo clearance and in vitro uptake by a glycoprotein recognition system on reticuloendothelial cells. Cell 1978; 15(1): 269–78

    Article  PubMed  CAS  Google Scholar 

  136. Weigel PH, Yik JH. Glycans as endocytosis signals: the cases of the asialoglycoprotein and hyaluronan/chondroitin sulfate receptors. Biochim Biophys Acta 2002; 1572(2-3): 341–63

    Article  PubMed  CAS  Google Scholar 

  137. Jefferis R. Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol Sci 2009; 30(7): 356–62

    Article  PubMed  CAS  Google Scholar 

  138. Egleton RD, Mitchell SA, Huber JD, et al. Improved bioavailability to the brain of glycosylated Met-enkephalin analogs. Brain Res 2000; 881(1): 37–46

    Article  PubMed  CAS  Google Scholar 

  139. Egleton RD, Mitchell SA, Huber JD, et al. Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation. J Pharmacol Exp Ther 2001; 299(3): 967–72

    PubMed  CAS  Google Scholar 

  140. Kihlberg J, Ahman J, Walse B, et al. Glycosylated peptide hormones: pharmacological properties and conformational studies of analogues of [1-de-samino, 8-D-arginine]vasopressin. J Med Chem 1995; 38(1): 161–9

    Article  PubMed  CAS  Google Scholar 

  141. Haubner R, Wester HJ, Burkhart F, et al. Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics. J Nucl Med 2001; 42(2): 326–36

    PubMed  CAS  Google Scholar 

  142. Albert R, Marbach P, Bauer W, et al. SDZ CO 611: a highly potent glycated analog of somatostatin with improved oral activity. LifeSci 1993; 53(6): 517–25

    Article  CAS  Google Scholar 

  143. Halstenson CE, Macres M, Katz SA, et al. Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta. Clin Pharmacol Ther 1991; 50(6): 702–12

    Article  PubMed  CAS  Google Scholar 

  144. Sasayama S, Moriya K, Chiba T, et al. Glycosylated human interleukin-1alpha, neoglyco IL-1alpha, coupled with N-acetylneuraminic acid exhibits selective activities in vivo and altered tissue distribution. Glycoconj J 2000; 17(6): 353–9

    Article  PubMed  CAS  Google Scholar 

  145. Iwao Y, Hiraike M,,Kragh-Hansen U, et al. Altered chain-length and glycosylation modify the pharmacokinetics of human serum albumin. Biochim Biophys Acta 2009; 1794(4): 634–41

    Article  PubMed  CAS  Google Scholar 

  146. Millward TA, Heitzmann M, Bill K, et al. Effect of constant and variable domain glycosylation on pharmacokinetics of therapeutic antibodies in mice. Biologicals 2008; 36(1): 41–7

    Article  PubMed  CAS  Google Scholar 

  147. Sheffield WP, Marques JA, Bhakta V, et al. Modulation of clearance of recombinant serum albumin by either glycosylation or truncation. Thromb Res 2000; 99(6): 613–21

    Article  PubMed  CAS  Google Scholar 

  148. Cousin P, Dechaud H, Grenot C, et al. Influence of glycosylation on the clearance of recombinant human sex hormone-binding globulin from rabbit blood. J Steroid Biochem Mol Biol 1999; 70(4-6): 115–21

    Article  PubMed  CAS  Google Scholar 

  149. Burgon PG, Stanton PG, Robertson DM. In vivo bioactivities and clearance patterns of highly purified human luteinizing hormone isoforms. Endocrinology 1996; 137(11): 4827–36

    Article  PubMed  CAS  Google Scholar 

  150. Wawrzynczak EJ, Cumber AJ, Parnell GD, et al. Blood clearance in the rat of a recombinant mouse monoclonal antibody lacking the N-linked oligo-saccharide side chains of the CH2 domains. Mol Immunol 1992; 29(2): 213–20

    Article  PubMed  CAS  Google Scholar 

  151. Henkin J, Dudlak D, Beebe DP, et al. High sialic acid content slows prour-okinase turnover in rabbits. Thromb Res 1991; 63(2): 215–25

    Article  PubMed  CAS  Google Scholar 

  152. Kawatsu M, Takeo K, Kajikawa T, et al. The pharmacokinetic pattern of glycosylated human recombinant lymphotoxin (LT) in rats after intravenous administration. J Pharmacobiodyn 1990; 13(9): 549–57

    Article  PubMed  CAS  Google Scholar 

  153. Gross V, Steube K, Tran-Thi T, et al. The role of N-glycosylation for the plasma clearance of rat liver secretory glycoproteins. Eur J Biochem 1987; 162(1): 83–8

    Article  PubMed  CAS  Google Scholar 

  154. Kim HJ, Lee DH, Kim DK, et al. The glycosylation and in vivo stability of human granulocyte-macrophage colony-stimulating factor produced in rice cells. Biol Pharm Bull 2008; 31(2): 290–4

    Article  PubMed  CAS  Google Scholar 

  155. Denis CV, Christophe OD, Oortwijn BD, et al. Clearance of von Willebrand factor. Thromb Haemost 2008; 99(2): 271–8

    PubMed  CAS  Google Scholar 

  156. Millar CM, Riddell AF, Brown SA, et al. Survival of von Willebrand factor released following DDAVP in a type 1 von Willebrand disease cohort: influence of glycosylation, proteolysis and gene mutations. Thromb Haemost 2008; 99(5): 916–24

    PubMed  CAS  Google Scholar 

  157. Smith WB, Dowell JA, Pratt RD. Pharmacokinetics and pharmacodynamics of epoetin delta in two studies in healthy volunteers and two studies in patients with chronic kidney disease. Clin Ther 2007; 29(7): 1368–80

    Article  PubMed  CAS  Google Scholar 

  158. Jones AJ, Papac DI, Chin EH, et al. Selective clearance of glycoforms of a complex glycoprotein pharmaceutical caused by terminal N-acetylglucosamine is similar in humans and cynomolgus monkeys. Glycobiology 2007; 17(5): 529–40

    Article  PubMed  CAS  Google Scholar 

  159. Perlman S, van denHazel B, Christiansen J, et al. Glycosylation of an N-terminal extension prolongs the half-life and increases the in vivo activity of follicle stimulating hormone. J Clin Endocrinol Metab 2003; 88(7): 3227–35

    Article  PubMed  CAS  Google Scholar 

  160. Barrios-De-Tomasi J, Timossi C, Merchant H, et al. Assessment of the in vitro and in vivo biological activities of the human follicle-stimulating isohormones. Mol Cell Endocrinol 2002; 186(2): 189–98

    Article  PubMed  CAS  Google Scholar 

  161. Macdougall IC. Optimizing the use of erythropoietic agents: pharmacokinetic and pharmacodynamic considerations. Nephrol Dial Transplant 2002; 17 Suppl. 5: 66–70

    Article  Google Scholar 

  162. Ni H, Blajchman MA, Ananthanarayanan VS, et al. Mutation of any site of N-linked glycosylation accelerates the in vivo clearance of recombinant rabbit antithrombin. Thromb Res 2000; 99(4): 407–15

    Article  PubMed  CAS  Google Scholar 

  163. Marinaro JA, Casley DJ, Bach LA. O-glycosylation delays the clearance of human IGF-binding protein-6 from the circulation. Eur J Endocrinol 2000; 142(5): 512–6

    Article  PubMed  CAS  Google Scholar 

  164. Chitlaru T, Kronman C, Zeevi M, et al. Modulation of circulatory residence of recombinant acetylcholinesterase through biochemical or genetic manipulation of sialylation levels. Biochem J 1998; 336 (Pt 3): 647–58

    PubMed  CAS  Google Scholar 

  165. Saxena A, Raveh L, Ashani Y, et al. Structure of glycan moieties responsible for the extended circulatory life time of fetal bovine serum acetylcholinesterase and equine serum butyrylcholinesterase. Biochemistry 1997; 36(24): 7481–9

    Article  PubMed  CAS  Google Scholar 

  166. Thotakura NR, Szkudlinski MW, Weintraub BD. Structure-function studies of oligosaccharides of recombinant human thyrotrophin by sequential de-glycosylation and resialylation. Glycobiology 1994; 4(4): 525–33

    Article  PubMed  CAS  Google Scholar 

  167. Otter M, Kuiper J, vanBerkel TJ, et al. Mechanisms of tissue-type plasminogen activator (tPA) clearance by the liver. Ann N Y Acad Sci 1992; 667: 431–42

    Article  PubMed  CAS  Google Scholar 

  168. Wasley LC, Timony G, Murtha P, et al. The importance of N- and O-linked oligosaccharides for the biosynthesis and in vitro and in vivo biologic activities of erythropoietin. Blood 1991; 77(12): 2624–32

    PubMed  CAS  Google Scholar 

  169. Galway AB, Hsueh AJ, Keene JL, et al. In vitro and in vivo bioactivity of recombinant human follicle-stimulating hormone and partially deglycosylated variants secreted by transfected eukaryotic cell lines. Endocrinology 1990; 127(1): 93–100

    Article  PubMed  CAS  Google Scholar 

  170. Lucore CL, Fry ET, Nachowiak DA, et al. Biochemical determinants of clearance of tissue-type plasminogen activator from the circulation. Circulation 1988; 77(4): 906–14

    Article  PubMed  CAS  Google Scholar 

  171. Mirshahi M, Soria J, Soria C, et al. Glycosylation of human fibrinogen and fibrin in vitro: its consequences on the properties of fibrin (ogen). Thromb Res 1987; 48(3): 279–89

    Article  PubMed  CAS  Google Scholar 

  172. Elliott S, Egrie J, Browne J, et al. Control of rHuEPO biological activity: the role of carbohydrate. Exp Hematol 2004; 32(12): 1146–55

    Article  PubMed  CAS  Google Scholar 

  173. Negri L, Melchiorri P, Rocchi R, et al. Opioid receptor affinity and analgesic activity of O- and C-glycosylated opioid peptides. Acta Physiol Hung 1996; 84(4): 441–3

    PubMed  CAS  Google Scholar 

  174. Fishburn CS. The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. J Pharm Sci 2008; 97(10): 4167–83

    Article  PubMed  CAS  Google Scholar 

  175. Raju TS. Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr Opin Immunol 2008; 20(4): 471–8

    Article  PubMed  CAS  Google Scholar 

  176. Crispin M, Bowden TA, Coles CH, et al. Carbohydrate and domain architecture of an immature antibody glycoform exhibiting enhanced effector functions. J Mol Biol 2009; 387(5): 1061–6

    Article  PubMed  CAS  Google Scholar 

  177. Barbey F, Hayoz D, Widmer U, et al. Efficacy of enzyme replacement therapy in Fabry disease. Curr Med Chem Cardiovasc Hematol Agents 2004; 2(4): 277–86

    Article  PubMed  CAS  Google Scholar 

  178. Beck M. Agalsidase alfa for the treatment of Fabry disease: new data on clinical efficacy and safety. Expert Opin Biol Ther 2009; 9(2): 255–61

    Article  PubMed  CAS  Google Scholar 

  179. Lee K, Jin X, Zhang K, et al. A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease. Glycobiology 2003; 13(4): 305–13

    Article  PubMed  Google Scholar 

  180. Keating GM, Simpson D. Spotlight on agalsidase beta in Fabry disease. Biodrugs 2007; 21(4): 269–71

    Article  PubMed  CAS  Google Scholar 

  181. Keating GM, Simpson D. Agalsidase beta: a review of its use in the management of Fabry disease. Drugs 2007; 67(3): 435–55

    Article  PubMed  CAS  Google Scholar 

  182. Jurado Garcia JM, Torres Sanchez E, Olmos Hidalgo D, et al. Erythropoietin pharmacology. Clin Transl Oncol 2007; 9(11): 715–22

    Article  CAS  Google Scholar 

  183. Takeuchi M, Kobata A. Structures and functional roles of the sugar chains of human erythropoietins. Glycobiology 1991; 1(4): 337–46

    Article  PubMed  CAS  Google Scholar 

  184. Weenen C, Pena JE, Pollak SV, et al. Long-acting follicle-stimulating hormone analogs containing N-linked glycosylation exhibited increased bioactivity compared with o-linked analogs in female rats. J Clin Endocrinol Metab 2004; 89(10): 5204–12

    Article  PubMed  CAS  Google Scholar 

  185. Creus S, Chaia Z, Pellizzari EH, et al. Human FSH isoforms: carbohydrate complexity as determinant of in-vitro bioactivity. Mol Cell Endocrinol 2001; 174(1-2): 41–9

    Article  PubMed  CAS  Google Scholar 

  186. leCotonnec JY, Loumaye E, Porchet HC, et al. Pharmacokinetic and pharmacodynamic interactions between recombinant human luteinizing hormone and recombinant human follicle-stimulating hormone. Fertil Steril 1998; 69(2): 201–9

    Article  PubMed  Google Scholar 

  187. leCotonnec JY, Porchet HC, Beltrami V, et al. Clinical pharmacology of recombinant human luteinizing hormone, part II: bioavailability of recombinant human luteinizing hormone assessed with an immunoassay and an in vitro bioassay. Fertil Steril 1998; 69(2): 195–200

    Article  PubMed  Google Scholar 

  188. leCotonnec JY, Porchet HC, Beltrami V, et al. Clinical pharmacology of recombinant human luteinizing hormone, part I: pharmacokinetics after intravenous administration to healthy female volunteers and comparison with urinary human luteinizing hormone. Fertil Steril 1998; 69(2): 189–94

    Article  PubMed  Google Scholar 

  189. Klett D, Bernard S, Lecompte F, et al. Fast renal trapping of porcine luteinizing hormone (pLH) shown by 123I-scintigraphic imaging in rats explains its short circulatory half-life. Reprod Biol Endocrinol 2003; 1: 64

    Google Scholar 

  190. Dhillon S, Keating GM. Lutropin alfa. Drugs 2008; 68(11): 1529–40

    Article  PubMed  CAS  Google Scholar 

  191. Baenziger JU, Kumar S, Brodbeck RM, et al. Circulatory half-life but not interaction with the lutropin/chorionic gonadotropin receptor is modulated by sulfation of bovine lutropin oligosaccharides. Proc Natl Acad Sci U S A 1992; 89(1): 334–8

    Article  PubMed  CAS  Google Scholar 

  192. Wakefield LM, Winokur TS, Hollands RS, et al. Recombinant latent transforming growth factor beta 1 has a longer plasma half-life in rats than active transforming growth factor beta 1, and a different tissue distribution. J Clin Invest 1990; 86(6): 1976–84

    Article  PubMed  CAS  Google Scholar 

  193. Hoglund M. Glycosylated and non-glycosylated recombinant human granulocyte colony-stimulating factor (rhG-CSF): what is the difference? Med Oncol 1998; 15(4): 229–33

    Article  PubMed  CAS  Google Scholar 

  194. Hovgaard D, Mortensen BT, Schifter S, et al. Comparative pharmacokinetics of single-dose administration of mammalian and bacterially-derived recombinant human granulocyte-macrophage colony-stimulating factor. Eur J Haematol 1993; 50(1): 32–6

    Article  PubMed  CAS  Google Scholar 

  195. Sylvester RK. Clinical applications of colony-stimulating factors: a historical perspective. Am J Health Syst Pharm 2002; 59(7 Suppl. 2): S6–12

    PubMed  CAS  Google Scholar 

  196. Ziltener HJ, Clark-Lewis I, Jones AT, et al. Carbohydrate does not modulate the in vivo effects of injected interleukin-3. Exp Hematol 1994; 22(11): 1070–5

    PubMed  CAS  Google Scholar 

  197. Fukushima K, Watanabe H, Takeo K, et al. N-linked sugar chain structure of recombinant human lymphotoxin produced by CHO cells: the functional role of carbohydrate as to its lectin-like character and clearance velocity. Arch Biochem Biophys 1993; 304(1): 144–53

    Article  PubMed  CAS  Google Scholar 

  198. Minta JO. The role of sialic acid in the functional activity and the hepatic clearance of C1-INH. J Immunol 1981; 126(1): 245–9

    PubMed  CAS  Google Scholar 

  199. Longhurst H. Rhucin, a recombinant C1 inhibitor for the treatment of hereditary angioedema and cerebral ischemia. Curr Opin Investig Drugs 2008; 9(3): 310–23

    PubMed  CAS  Google Scholar 

  200. vanDoorn MB, Burggraaf J, van Dam T, et al. A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol 2005; 116(4): 876–83

    Article  PubMed  CAS  Google Scholar 

  201. Raju TS, Scallon BJ. Glycosylation in the Fc domain of IgG increases resistance to proteolytic cleavage by papain. Biochem Biophys Res Commun 2006; 341(3): 797–803

    Article  PubMed  CAS  Google Scholar 

  202. Dissing-Olesen L, Thaysen-Andersen M, Meldgaard M, et al. The function of the human interferon-beta 1a glycan determined in vivo. J Pharmacol Exp Ther 2008; 326(1): 338–47

    Article  PubMed  CAS  Google Scholar 

  203. Bocci V, Di Francesco P, Pacini A, et al. Renal metabolism of homologous serum interferon. Antiviral Res 1983; 3(1): 53–8

    Article  PubMed  CAS  Google Scholar 

  204. Iino M, Foster DC, Kisiel W. Functional consequences of mutations in Ser-52 and Ser-60 in human blood coagulation factor VII. Arch Biochem Biophys 1998; 352(2): 182–92

    Article  PubMed  CAS  Google Scholar 

  205. Lillicrap D. Extending half-life in coagulation factors: where do we stand? Thromb Res 2008; 122 Suppl. 4: S2–8

    Article  CAS  Google Scholar 

  206. Jain S, Hreczuk-Hirst DH, McCormack B, et al. Polysialylated insulin: synthesis, characterization and biological activity in vivo. Biochim Biophys Acta 2003; 1622(1): 42–9

    Article  PubMed  CAS  Google Scholar 

  207. Gregoriadis G, Fernandes A, McCormack B, et al. Polysialic acids: potential role in therapeutic constructs. Biotechnol Genet Eng Rev 1999; 16: 203–15

    PubMed  CAS  Google Scholar 

  208. Gregoriadis G, Fernandes A, Mital M, et al. Polysialic acids: potential in improving the stability and pharmacokinetics of proteins and other therapeutics. Cell Mol Life Sci 2000; 57(13-14): 1964–9

    Article  PubMed  CAS  Google Scholar 

  209. Stork R, Zettlitz KA, Muller D, et al. N-glycosylation as novel strategy to improve pharmacokinetic properties of bispecific single-chain diabodies. J Biol Chem 2008; 283(12): 7804–12

    Article  PubMed  CAS  Google Scholar 

  210. Fernandes AI, Gregoriadis G. Polysialylated asparaginase: preparation, activity and pharmacokinetics. Biochim Biophys Acta 1997; 1341(1): 26–34

    Article  PubMed  CAS  Google Scholar 

  211. Fernandes AI, Gregoriadis G. The effect of polysialylation on the immunogenicity and antigenicity of asparaginase: implication in its pharmacokinetics. Int J Pharm 2001; 217(1-2): 215–24

    Article  PubMed  CAS  Google Scholar 

  212. Jelkmann W. The enigma of the metabolic fate of circulating erythropoietin (Epo) in view of the pharmacokinetics of the recombinant drugs rhEpo and NESP. Eur J Haematol 2002; 69(5-6): 265–74

    Article  PubMed  CAS  Google Scholar 

  213. Egrie JC, Dwyer E, Browne JK, et al. Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Exp Hematol 2003; 31(4): 290–9

    Article  PubMed  CAS  Google Scholar 

  214. Gross AW, Lodish HF. Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem 2006; 281(4): 2024–32

    Article  PubMed  CAS  Google Scholar 

  215. Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood 2002; 100(10): 3457–69

    Article  PubMed  CAS  Google Scholar 

  216. Ruman JI, Pollak S, Trousdale RK, et al. Effects of long-acting recombinant human follicle-stimulating hormone analogs containing N-linked glycosylation on murine folliculogenesis. Fertil Steril 2005; 83 Suppl. 1: 1303–9

    Article  CAS  Google Scholar 

  217. Trousdale RK, Yu B, Pollak SV, et al. Efficacy of native and hyperglycosylated follicle-stimulating hormone analogs for promoting fertility in female mice. Fertil Steril 2009; 91(1): 265–70

    Article  PubMed  CAS  Google Scholar 

  218. Fauser BC, Mannaerts BM, Devroey P, et al. Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency. Hum Reprod Update 2009; 15(3): 309–21

    Article  PubMed  CAS  Google Scholar 

  219. Loutradis D, Drakakis P, Vlismas A, et al. Corifollitropin alfa, a long-acting follicle-stimulating hormone agonist for the treatment of infertility. Curr Opin Investig Drugs 2009; 10(4): 372–80

    PubMed  CAS  Google Scholar 

  220. Balen AH, Mulders AG, Fauser BC, et al. Pharmacodynamics of a single low dose of long-acting recombinant follicle-stimulating hormone (FSH-car-boxy terminal peptide, corifollitropin alfa) in women with World Health Organization group II anovulatory infertility. J Clin Endocrinol Metab 2004; 89(12): 6297–304

    Article  PubMed  CAS  Google Scholar 

  221. Devroey P, Fauser BC, Platteau P, et al. Induction of multiple follicular development by a single dose of long-acting recombinant follicle-stimulating hormone (FSH-CTP, corifollitropin alfa) for controlled ovarian stimulation before in vitro fertilization. J Clin Endocrinol Metab 2004; 89(5): 2062–70

    Article  PubMed  CAS  Google Scholar 

  222. Duijkers IJ, Klipping C, Boerrigter PJ, et al. Single dose pharmacokinetics and effects on follicular growth and serum hormones of a long-acting recombinant FSH preparation (FSH-CTP) in healthy pituitary-suppressed females. Hum Reprod 2002; 17(8): 1987–93

    Article  PubMed  CAS  Google Scholar 

  223. Wraith JE. Lysosomal disorders. Semin Neonatol 2002; 7(1): 75–83

    Article  PubMed  CAS  Google Scholar 

  224. Pohl S, Marschner K, Storch S, et al. Glycosylation- and phosphorylation-dependent intracellular transport of lysosomal hydrolases. Biol Chem 2009; 390(7): 521–7

    Article  PubMed  CAS  Google Scholar 

  225. Kornfeld S. Lysosomal enzyme targeting. Biochem Soc Trans 1990; 18(3): 367–74

    PubMed  CAS  Google Scholar 

  226. Grabowski GA, Hopkin RJ. Enzyme therapy for lysosomal storage disease: principles, practice, and prospects. Annu Rev Genomics Hum Genet 2003; 4: 403–36

    Article  PubMed  CAS  Google Scholar 

  227. Murray GJ. Lectin-specific targeting of lysosomal enzymes to reticuloendo-thelial cells. Methods Enzymol 1987; 149: 25–42

    Article  PubMed  CAS  Google Scholar 

  228. Stahl PD, Rodman JS, Miller MJ, et al. Evidence for receptor-mediated binding of glycoproteins, glycoconjugates, and lysosomal glyco-sidases by alveolar macrophages. Proc Natl Acad Sci U S A 1978; 75(3): 1399–403

    Article  PubMed  CAS  Google Scholar 

  229. Furbish FS, Steer CJ, Barranger JA, et al. The uptake of native and desialy-lated glucocerebrosidase by rat hepatocytes and Kupffer cells. Biochem Biophys Res Commun 1978; 81(3): 1047–53

    Article  PubMed  CAS  Google Scholar 

  230. Furbish FS, Steer CJ, Krett NL, et al. Uptake and distribution of placental glucocerebrosidase in rat hepatic cells and effects of sequential deglycosylation. Biochim Biophys Acta 1981; 673(4): 425–34

    Article  PubMed  CAS  Google Scholar 

  231. Steer CJ, Furbish FS, Barranger JA, et al. The uptake of agalacto-glucocerebrosidase by rat hepatocytes and Kupffer cells. FEBS Lett 1978; 91(2): 202–5

    Article  PubMed  CAS  Google Scholar 

  232. McVie-Wylie AJ, Lee KL, Qiu H, et al. Biochemical and pharmacological characterization of different recombinant acid alpha-glucosidase preparations evaluated for the treatment of Pompe disease. Mol Genet Metab 2008; 94(4): 448–55

    Article  PubMed  CAS  Google Scholar 

  233. Hopwood JJ, Bate G, Kirkpatrick P. Galsulfase. Nat Rev Drug Discov 2006; 5(2): 101–2

    Article  PubMed  CAS  Google Scholar 

  234. Turner CT, Hopwood JJ, Brooks DA. Enzyme replacement therapy in mucopolysaccharidosis I: altered distribution and targeting of alpha-L-iduronidase in immunized rats. Mol Genet Metab 2000; 69(4): 277–85

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This review was made possible by a grant to K.G. (SC1 GM086240) from the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health (NIH) through the SCORE (Support of Competitive Research) program. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS. The authors have no conflicts of interest that are directly relevant to the contents of this review.

Author information

Authors and Affiliations

  1. Laboratory for Applied Biochemistry and Biotechnology, Department of Chemistry, University of Puerto Rico, Río Piedras Campus, PO Box 23346, San Juan, Puerto Rico, Puerto Rico, 00931-3346, USA

    Ricardo J. Solá & Kai Griebenow

Authors
  1. Ricardo J. Solá
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai Griebenow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ricardo J. Solá.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Solá, R.J., Griebenow, K. Glycosylation of Therapeutic Proteins. BioDrugs 24, 9–21 (2010). https://doi.org/10.2165/11530550-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11530550-000000000-00000

Keywords

Search

Navigation