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  • Review Article
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The Oligosaccharides of Glycoproteins: Bioprocess Factors Affecting Oligosaccharide Structure and their Effect on Glycoprotein Properties

Abstract

In this review, we organize the recent data concerning the effects of bioprocess factors on the oligosaccharide structure of human therapeutic glycoproteins, with particular emphasis on the influence of the host cell. We also discuss the effect of oligosaccharide structure on glycoprotein properties, including antigenicity, immunogenicity and plasma clearance rate.

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Ieva Bagdonaite, Stacy A. Malaker, … Nichollas E. Scott

References

  1. Rademacher, T.W., Parekh, R.B. and Dwek, R.A. 1988. Glycobiology. Ann. Rev. Biochem. 57: 785–838.

    CAS  PubMed  Google Scholar 

  2. Goochee, C.F. and Monica, T. 1990. Environmental effects on protein glycosylation, Bio/Technology 8: 421–427.

    CAS  PubMed  Google Scholar 

  3. Goochee, C.F., Gramer, M., Andersen, D., Bahr, J. and Rasmussen, J.R. 1991. The oligosaccharides of glycoproteins: factors affecting their synthesis and their influence on glycoprotein properties, p. 199–240. In: Frontiers in Bioprocessing II, S. K. Sikdar, M. Bier, and P. Todd, (Eds.). American Chemical Society, Washington, D.C.

    Google Scholar 

  4. Kornfeld, R. and Kornfeld, S. 1985. Assembly of asparagine-linked oligosaccharides. Ann. Rev. Biochem. 54: 631–664.

    CAS  PubMed  Google Scholar 

  5. Gavel, Y. and von Heijne, G. 1990. Sequence differences between glycosylated and non-glycosylated Asn-X-Thr/Ser acceptor sites: implications for protein engineering. Protein Engineering 3: 433–442.

    CAS  PubMed  Google Scholar 

  6. Miletich, J.P. and Broze, G.J. 1990. β Protein C is not glycosylated at asparagine 329. J. Biol. Chem. 265: 11397–11404.

    CAS  PubMed  Google Scholar 

  7. Kaushal, G.P., Szumilo, T. and Elbein, A.D. 1988. Structure and biosynthesis of plant N-linked glycoproteins. Biochem. of Plants 14: 421–463.

    CAS  Google Scholar 

  8. Kukuruzinska, M.A., Bergh, M.L.E. and Jackson, B.J. 1987. Protein glycosylation in yeast. Ann. Rev. Biochem. 56: 915–944.

    CAS  PubMed  Google Scholar 

  9. Tanner, W. and Lehle, L. 1987. Protein glycosylation in yeast. Biochim. Biophys. Acta 906: 81–99.

    CAS  PubMed  Google Scholar 

  10. Leonard, C.K., Spellman, M.W., Riddle, L., Harris, R.J., Thomas, J.N. and Gregory, T.J. 1990. Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. J. Biol. Chem. 265: 10373–10382.

    CAS  PubMed  Google Scholar 

  11. Hitzman, R.A., Chen, C.Y., Dowbenko, D.J., Renz, M.E., Liu, C., Pai, R., Simpson, N.J., Kohr, W.J., Singh, A., Chisholm, V., Hamilton, R. and Chang, C.N. 1990. Use of heterologous and homologous signal sequences for secretion of heterologous proteins from yeast. Methods in Enzymol. 185: 421–440.

    Google Scholar 

  12. Ballou, C.E. 1990. Isolation, characterization, and properties of Saccharomyces cerevisiae mnn mutants with nonconditional protein glycosylation defects. Methods in Enzymol. 185: 440–469.

    CAS  Google Scholar 

  13. Kuroda, K., Geyer, H., Geyer, R., Doerfler, W. and Klenk, H.-D. 1990. The oligosaccharides of influenza virus hemagglutinin expressed in insect cells by a baculovirus vector. Virology 174: 418–429.

    CAS  PubMed  Google Scholar 

  14. Lin, R.K., Suggs, S., Lin, C.-H., Browne, J.K., Smalling, R., Egrie, J.C., Chen, K.K., Fox, G.M., Martin, F., Stabinsky, Z., Badrawi, S.M., Lai, P.-H. and Goldwasser, E. 1985. Cloning and expression of the human erythropoietin gene. Proc. Natl. Acad. Sci. 82: 7580–7584.

    CAS  PubMed  Google Scholar 

  15. Jacobs, K., Shoemaker, C., Rudersdorf, R., Neill, S.D., Kaufman, R.J., Mufson, A., Seehra, J., Jones, S.S., Hewick, R., Fritsch, E.F., Kawakita, M., Shimizu, T. and Miyake, T. 1985. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 313: 806–810.

    CAS  PubMed  Google Scholar 

  16. Imai, N., Kawamura, A., Higuchi, M., Oh-eda, M., Orita, T., Kawaguchi, T. and Ochi, N. 1990. Physiochemical and biological comparison of recombinant human erythropoietin with human urinary erythropoietin. J. Biochem. 107: 352–359.

    CAS  PubMed  Google Scholar 

  17. Quelle, F.W., Caslake, L.F., Burkert, R.E. and Wojchowski, D.M. 1989. High-level expression and purification of a recombinant human erythropoietin produced using a baculovirus vector. Blood 74: 652–657.

    CAS  PubMed  Google Scholar 

  18. Steiner, H., Pohl, G., Gunne, H., Hellers, M., Elhammer, A. and Hansson, L. 1988. Human tissue-type plasminogen activator synthesized by using a baculovirus vector in insect cells compared with human plasminogen activator produced in mouse cells. Gene 73: 449–457.

    CAS  PubMed  Google Scholar 

  19. Itoh, K., Oshima, A., Sakuraba, H. and Suzuki, Y. 1990. Expression, glycosylation, and intracellular distribution of human β-galactosidase in recombinant baculovirus-infected Spodoptera frugiperda cells. Biochem. Biophys. Res. Comm. 167: 746–753.

    CAS  PubMed  Google Scholar 

  20. Smith, G.E., Summers, M.D. and Fraser, M.J. 1983. Production of human beta interferon in insect cells infected with a baculovirus expression vector. Mol. Cell. Biol. 3: 2156–2165.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Davidson, D.J. and Castellino, F.J. 1991. Asparagine-linked oligosaccharide processing in Lepidopteran insect cells. Temporal dependence of the nature of the oligosaccharides assembled on asparagine-289 of recombinant human plasminogen produced in baculovirus vector-infected Spodoptera frugiperda (IPLB-SF-21AE) cells. Biochem. 30: 6167–6174.

    CAS  Google Scholar 

  22. March, C.J., Mosley, B., Larsen, A., Cerretti, D.P., Braedt, G., Price, V., Gillis, S., Henney, C.S., Kronheim, S.R., Grabstein, K., Conlon, P.J., Hopp, T.P. and Cosman, D. 1985. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature 315: 641–647.

    CAS  PubMed  Google Scholar 

  23. Casagli, M.C., Borri, M.G., Bigio, M., Rossi, R., Nucci, D., Bossu, P., Boraschi, D. and Antoni, G. 1989. Different conformation of purified human recombinant interleukin 1β from Escherichia coli and Saccharomyces cerevisiae is related to different level of biological activity. Biochem. Biophys. Res. Comm. 162: 357–363.

    CAS  PubMed  Google Scholar 

  24. Livi, G.P., Ferrara, A., Roskin, R., Simon, P.L. and Young, P.R. 1990. Secretion of N-glycosylated human recombinant interleukin-1α in Saccharomyces cerevisiae. Gene 88: 297–301.

    CAS  PubMed  Google Scholar 

  25. Sadler, J.E. Biosynthesis of glycoproteins: formation of O-linked oligosaccharides, Chapter 4. In: Biology of Carbohydrates, V. 2, V. Ginsburg and P. W. Robbins (Eds.). John Wiley & Sons, NY.

  26. Carraway, K.L. and Hull, S.R. 1989. O-Glycosylation pathway of mucin-type glycoproteins. BioEssays 10: 117–121.

    CAS  PubMed  Google Scholar 

  27. Conradt, H.S., Geyer, R., Hoppe, J., Grotjahn, L., Plessing, A. and Mohr, H. 1985. Structures of the major carbohydrates of natural human interleukin-2. Eur. J. Biochem. 153: 255–261.

    CAS  PubMed  Google Scholar 

  28. Conradt, H.S., Nimtz, M., Dittmar, K.E.J., Lindenmaier, W., Hoppe, J. and Hauser, H. 1989. Expression of human interleukin-2 in recombinant baby hamster kidney, Ltk, and Chinese hamster ovary cells. J. Biol. Chem. 264: 17368–17373.

    CAS  PubMed  Google Scholar 

  29. Tsuda, E., Kawanishi, G., Ueda, M., Masuda, S. and Sasaki, R. 1990. The role of carbohydrate in recombinant human erythropoietin. Eur. J. Biochem. 188: 405–411.

    CAS  PubMed  Google Scholar 

  30. Field, M.C., Dwek, R.A., Edge, C.J. and Rademacher, T.W. 1989. O-linked oligosaccharides from human serum immunoglobulin A1. Biochem. Soc. Trans. 17: 1034–1035.

    CAS  PubMed  Google Scholar 

  31. Oheda, M., Hase, S., Ono, M. and Ikenaka, T. 1988. Structures of the sugar chains of recombinant human granulocyte-colony-stimulating factor produced by Chinese hamster ovary cells. J. Biochem. 103: 544–546.

    CAS  PubMed  Google Scholar 

  32. Marti, T., Schaller, J., Rickli, E.E., Schmid, K., Kamerling, J.P., Gerwig, G.J., van Halbeek, H. and Vliegenthart, J.F.G. 1988. The N-linked and O-linked carbohydrate chains of human, bovine and porcine plasminogen. Eur. J. Biochem. 173: 57–63.

    CAS  PubMed  Google Scholar 

  33. Hard, K., Bitter, W., Kamerling, J.P. and Vliegenthart, J.F.G. 1989. O-mannosylation of recombinant human insulin-like growth factor I (IGF-I) produced in Saccharomyces cerevisiae. FEBS Lett. 248: 111–114.

    CAS  PubMed  Google Scholar 

  34. Gellerfors, P., Axelsson, K., Helander, A., Johansson, S., Kenne, L., Lindqvist, S., Pavlu, B., Skottner, A. and Fryklund, L. 1989. Isolation and characterization of a glycosylated form of human insulin-like growth factor I produced in Saccharomyces cerevisiae. J. Biol. Chem. 264: 11444–11449.

    CAS  PubMed  Google Scholar 

  35. Elliott, S., Fagin, K.D., Narhi, L.O., Miller, J.A., Jones, M., Koski, R., Peters, M., Hsieh, P., Sachdev, R., Rosenfeld, R.D., Rohde, M.F. and Arakawa, T. 1990. Yeast-derived recombinant human insulin-like growth factor I: production, purification, and structural characterization. J. Protein Chemistry 9: 95–104.

    CAS  Google Scholar 

  36. Thomsen, D.R., Post, L.E. and Elhammer, A.P. 1990. Structure of O-glycosidically linked oligosaccharides synthesized by the insect cell line Sf9. J. Cell. Biochem. 43: 67–79.

    CAS  PubMed  Google Scholar 

  37. Smith, G.E., Ju, G., Ericson, B.L., Moschera, J., Lahm, H.-W., Chizzonite, R. and Summers, M.D. 1985. Modification and secretion of human interleukin 2 produced in insect cells by a baculovirus expression system. Proc. Natl. Acad. Sci. 82: 8404–8408.

    CAS  PubMed  Google Scholar 

  38. Kobata, A. 1984. The carbohydrates of glycoproteins, Chapter 2. In: Biology of Carbohydrates, V. 2, V. Ginsburg and P. W. Robbins (Eds.). John Wiley & Sons, NY.

    Google Scholar 

  39. Paulson, J.C. 1989. Glycoproteins: what are the sugar chains for? Trends in Biochemical Sciences 14: 272–276.

    CAS  PubMed  Google Scholar 

  40. Paulson, J.C. and Colley, K.J. 1989. Glycosyltransferases. J. Biol. Chem. 264: 17615–17618.

    CAS  PubMed  Google Scholar 

  41. Parekh, R.B., Dwek, R.A., Thomas, J.R., Opdenakker, G., Rademacher, T., Wittwer, A.J., Howard, S.C., Nelson, R., Siegel, N.R., Jennings, M.G., Harakas, N.K. and Feder, J. 1989. Cell-type-specific and site-specific N-glycosylation of type I and type II human tissue plasminogen activator. Biochem. 28: 7644–7662.

    CAS  Google Scholar 

  42. Galili, U., Shohet, S.B., Kobrin, E., Stults, C.L.M. and Macher, B.A. 1988. Man, apes, and old world monkeys differ from other mammals in the expression of α-galactosyl epitopes on nucleated cells. J. Biol. Chem. 263: 17755–17762.

    CAS  PubMed  Google Scholar 

  43. Thall, A. and Galili, U. 1990. Distribution of Galα(1,3)Galβ(1,4)-GlcNAc residues on secreted mammalian glycoproteins (thyroglobulin, fibrinogen, and immunoglobulin G) as measured by a sensitive solid-phase radioimmunoassay. Biochem. 29: 3959–3965.

    CAS  Google Scholar 

  44. Kagawa, Y., Takasaki, S., Utsumi, J., Hosoi, K., Shimizu, H., Kochibe, N. and Kobata, A. 1988. Comparatives study of the asparagine-linked sugar chains of natural human interferon-β1 and recombinant human interferon-β1 produced by three different mammalian cells. J. Biol. Chem. 263: 17508–17515.

    CAS  PubMed  Google Scholar 

  45. Pfeiffer, G., Schmidt, M., Strube, K.-H. and Geyer, R. 1989. Carbohydrate structure of recombinant human uterine tissue plasminogen activator expressed in mouse epithelial cells. Eur. J. Biochem. 186: 273–286.

    CAS  PubMed  Google Scholar 

  46. Sasaki, H., Ochi, N., Dell, A. and Fukuda, M. 1988. Site-specific glycosylation of human recombinant erythropoietin: analysis of glycopeptides or peptides at each glycosylation site by fast atom bombardment mass spectroscopy. Biochem. 27: 8618–8626.

    CAS  Google Scholar 

  47. Takeuchi, M., Takasaki, S., Miyazaki, H., Takashi, K., Hoshi, S., Kochibe, N. and Kobata, A. 1988. Comparative study of the asparagine-linked sugar chains of human erythropoietins purified from urine and the culture medium of recombinant Chinese hamster ovary cells. J. Biol. Chem. 263: 3657–3663.

    CAS  PubMed  Google Scholar 

  48. Spellman, M.W., Basa, L.J., Leonard, C.K., Chakel, J.A., O'Connor, J.V., Wilson, S. and van Halbeek, H. 1989. Carbohydrate structures of human tissue plasminogen activator expressed in Chinese hamster ovary cells, J. Biol. Chem. 264: 14100–14111.

    CAS  PubMed  Google Scholar 

  49. Tsuda, E., Goto, M., Murakami, A., Akai, K., Ueda, M., Kawanishi, G., Takahashi, N., Sasaki, R., Chiba, H., Ishihara, H., Mori, M., Tejima, S., Endo, S. and Arata, Y. 1988. Comparative structural study of N-linked oligosaccharides of urinary and recombinant erythropoietins. Biochem. 27: 5646–5654.

    CAS  Google Scholar 

  50. Smith, D.F., Larsen, R.D., Mattox, S., Lowe, J.B. and Cummings, R.D. 1990. Transfer and expression of a murine UDP-Gal: β-D-Galα1,3-galactosyltransferase gene in transfected Chinese hamster ovary cells. J. Biol. Chem. 265: 6225–6234.

    CAS  PubMed  Google Scholar 

  51. Tollefsen, S.E. and Rosenblum, J.L. 1988. Role of terminal fucose residues in clearance of human glycosylated a-amylase. Am. J. Physiol. 255: G374–G381.

    CAS  PubMed  Google Scholar 

  52. Campbell, C. and Stanley, P. 1983. Regulatory mutations in CHO cells induce expression of the mouse embryonic antigen SSEA-1. Cell 35: 303–309.

    CAS  PubMed  Google Scholar 

  53. Lee, E.U., Roth, J. and Paulson, J.C. 1989. Alteration of terminal glycosylation sequences on N-linked oligosaccharides of Chinese hamster ovary cells by expression of β-galactoside α2,6-sialyltransferase. J. Biol. Chem. 264: 13848–13855.

    CAS  PubMed  Google Scholar 

  54. Potvin, B., Kumar, R., Howard, D.R. and Stanley, P. 1990. Transfection of a human a-(1,3) fucosyltransferase gene into Chinese hamster ovary cells. J. Biol. Chem. 265: 1615–1622.

    CAS  PubMed  Google Scholar 

  55. Kobata, A. 1988. Structures, function and transformational changes of the sugar chains of glycohormones. J. Cell. Biochem. 37: 79–90.

    CAS  PubMed  Google Scholar 

  56. Palcic, M.M., Ripka, J., Kaur, K.J., Shoreibah, M., Hindsgaul, O. and Pierce, M.J. 1990. Regulation of N-acetylglucosaminyltransferase V activity: kinetic comparisons of parental, rous sarcoma virus-transformed BHK, and L-phytohemagglutinin-resistant BHK cells using synthetic substrates and an inhibitory substrate analog. J. Biol. Chem. 265: 6759–6769.

    CAS  PubMed  Google Scholar 

  57. Carlsson, S.R., Sasaki, H. and Fukuda, M. 1986. Structural variations of O-linked oligosaccharides present in leukosialin isolated from erythroid, myeloid, and T-lymphoid cell lines. J. Biol. Chem. 261: 12787–12795.

    CAS  PubMed  Google Scholar 

  58. Stanley, P. 1984. Glycosylation mutants of animal cells. Ann. Rev. Genet. 18: 525–552.

    CAS  PubMed  Google Scholar 

  59. Stanley, P. 1987. Biochemical characterization of animal cell glycosylation mutants. Methods in Enzymol. 138: 443–458.

    CAS  Google Scholar 

  60. Stanley, P. 1989. Chinese hamster ovary cell mutants with multiple glycosylation defects for production of glycoproteins with minimal carbohydrate heterogeneity. Mol. Cell. Biol. 9: 377–383.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang, X.C., O'Hanlon, T.P. and Lau, J.T.Y. 1989. Regulation of β-galactoside α2,6-sialyltransferase gene expression by dexamethasone. J. Biol. Chem. 264: 1854–1859.

    CAS  PubMed  Google Scholar 

  62. Larsen, R.D., Rajan, V.P., Ruff, M.M., Kukowska-Latallo, J., Cummings, R.D. and Lowe, J.B. 1989. Isolation of a cDNA encoding a murine UDPgalactose:β-D-galactosyl-1,4-N-acetyl-D-glucosaminide α-1,3-galactosyltransferase: expression cloning by gene transfer. Proc. Natl. Acad. Sci. USA. 86: 8227–8231.

    CAS  PubMed  Google Scholar 

  63. Conradt, H.S., Egge, H., Peter-Katalinic, J., Reiser, W., Siklosi, T. and Schaper, K. 1987. Structure of the carbohydrate moiety of human interferon-β secreted by a recombinant Chinese hamster ovary cell line. J. Biol. Chem. 262: 14600–14605.

    CAS  PubMed  Google Scholar 

  64. Oh-eda, M., Hasegawa, M., Hattori, K., Kuboniwa, H., Kojima, T., Orita, T., Tomonou, K., Yamazaki, T. and Ochi, N. 1990. O-linked sugar chains of human granulocyte colony-stimulating factor protect it against polymerization and denaturation allowing it to retain its biological activity. J. Biol. Chem. 265: 11432–11435.

    CAS  PubMed  Google Scholar 

  65. Dordal, M.S., Wang, F.F. and Goldwasser, E. 1985. The role of carbohydrate in erythropoietin action. Endocrinology 116: 2293–2299.

    CAS  PubMed  Google Scholar 

  66. Takeuchi, M., Takashi, K., Hoshi, S., Shimada, M. and Kobata, A. 1990. Role of sugar chains in the in vitro biological activity of human erythropoietin produced in recombinant Chinese hamster ovary cells. J. Biol. Chem. 265: 12127–12130.

    CAS  PubMed  Google Scholar 

  67. Hansen, L., Blue, Y., Barone, K., Collen, D. and Larsen, G.R. 1988. Functional effects of aspargine-linked oligosaccharides on natural and variant human tissue-type plasminogen activator. J. Biol. Chem. 263: 15713–15719.

    CAS  PubMed  Google Scholar 

  68. Wittwer, A.J. and Howard, S.C. 1990. Glycosylation at Asn-184 inhibits the conversion of single-chain to two-chain tissue-type plasminogen activator by plasmin, Biochem. 29: 4175–4180.

    CAS  Google Scholar 

  69. Feizi, T. and Childs, R.A. 1987. Carbohydrates as antigenic determinants of glycoproteins. Biochem. J. 245: 1–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Chew, W.H. and Theus, T.L. 1967. Candida precipitins. J. Immunol. 98: 220–224.

    CAS  PubMed  Google Scholar 

  71. Savolainen, J., Viander, M. and Koivikko, A. 1990. IgE-, IgA-, and IgG-antibody responses to carbohydrate and protein antigens of Candida albicans in asthmatic children. Allergy 40: 54–63.

    Google Scholar 

  72. Alexander, S. and Elder, J.H. 1984. Carbohydrate dramatically influences immune reactivity of antisera to viral glycoprotein antigens. Science 226: 1328–1330.

    CAS  PubMed  Google Scholar 

  73. Schauer, R. 1988. Sialic acids as antigenic determinants of complex carbohydrates. Adv. Exp. Med. Biol. 228: 47–72.

    CAS  PubMed  Google Scholar 

  74. Rebois, R.V. and Liss, M.T. 1987. Antibody binding to the β-subunit of deglycosylated chorionic gonadotropin converts the antagonist to an agonist. J. Biol. Chem. 262: 3891–3896.

    CAS  PubMed  Google Scholar 

  75. Hattori, M., Hachisu, T., Shimohigashi, Y. and Wakabayashi, K. 1988. Conformation of the β-subunit of deglycosylated human chorionic gonadotropin in the interaction at receptor sites. Mol. Cell. Endocrinol. 57: 17–23.

    CAS  PubMed  Google Scholar 

  76. Sairam, M.R., Linggen, J. and Bhargavi, G.N. 1988. Alterations in antigenic structure of gonadotropins following deglycosylation. Bio-science Reports 8: 271–278.

    CAS  Google Scholar 

  77. Kaluza, G., Rott, R. and Schwarz, R.T. 1980. Carbohydrate-induced conformational changes of semiliki forest virus glycoproteins determine antigenicity. Virology 102: 286–299.

    CAS  PubMed  Google Scholar 

  78. Kaladas, P.M., Goldberg, R. and Poretz, R.D. 1983. Rabbit anticarbohydrate antibody elicited by the lymphocyte mitogenic glycoprotein from Wistaria floribunda seeds. Mol. Immunol. 20: 727–735.

    CAS  PubMed  Google Scholar 

  79. Zopf, D.-A., Tsai, C.M. and Ginsburg, V. 1978. Antibodies against oligosaccharides coupled to proteins: characterization of carbohydrate specificity by radioimmune assay. Arch. Biochem. Biophys. 185: 61–71.

    CAS  PubMed  Google Scholar 

  80. Canaud, B., Polito-Bouloux, C., Garred, L.J., Rivory, J.-P., Donnadieu, P., Taib, J., Florence, P. and Mion, C. 1990. Recombinant human erythropoietin: 18 months' experience in hemodialysis patients. Am. J. Kidney Dis. 15: 169–175.

    CAS  PubMed  Google Scholar 

  81. Faulds, D. and Sorkin, E.M. 1989. Epoetin (recombinant human erythropoietin): a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in anaemia and the stimulation of erythropoiesis. Drugs 38: 863–899.

    CAS  PubMed  Google Scholar 

  82. Lim, V.S., Kirchner, P.T., Fangman, J., Richmond, J. and DeGowin, R.L. 1989. The safety and the efficacy of maintenance therapy of recombinant human erythropoietin in patients with renal insufficiency. Am. J. Kidney Dis. 14: 496–506.

    CAS  PubMed  Google Scholar 

  83. Moore, W.V. and Leppert, P. 1980. Role of aggregated human growth hormone (hGH) in development of antibodies to hGH. J. Clin. Endocrin. Metab. 51: 691–697.

    CAS  Google Scholar 

  84. Man, N.T., Cartwright, A.J., Andrews, K.M. and Morris, G.E. 1989. Treatment of human muscle creatine kinase with glutaraldehyde preferentially increases the immunogenicity of the native conformation and permits production of high-affinity monoclonal antibodies which recognize two distinct surface epitopes. J. Immunol. Methods 125: 251–259.

    CAS  PubMed  Google Scholar 

  85. Reichlin, M., Nisonoff, A. and Margoliash, E. 1970. Immunological activity of cytochrome c. J. Biol. Chem. 245: 947–954.

    CAS  PubMed  Google Scholar 

  86. Katre, N.V. 1990. Immunogenicity of recombinant IL-2 modified by covalent attachment of polyethylene glycol. J. Immunol. 144: 209–213.

    CAS  PubMed  Google Scholar 

  87. Thompson, J.A., Lee, D.J., Kidd, P., Rubin, E., Kaufman, J., Bonnem, E.M. and Fefer, A. 1989. Subcutaneous granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects. J. Clin. Oncol. 7: 629–637.

    CAS  PubMed  Google Scholar 

  88. Hawkins, M., Horning, S., Konrad, M., Anderson, S., Sielaff, K., Rosno, S., Schiesel, J., Davis, T., DeMets, D., Merigan, T. and Borden, E. 1985. Phase I evaluation of synthetic mutant of β-interferon. Cancer Res. 45: 5914–5920.

    CAS  PubMed  Google Scholar 

  89. Sarna, G., Pertcheck, M., Figlin, R. and Ardalan, B. 1986. Phase I study of recombinant β ser 17 interferon in the treatment of cancer. Cancer Treat. Rep. 70: 1365–1372.

    CAS  PubMed  Google Scholar 

  90. Konrad, M.W., Childs, A.L., Merigan, T.C. and Borden, E.C. 1987. Assessment of the antigenic response in humans to a recombinant mutant interferon beta. J. Clin. Immunol. 7: 365–375.

    CAS  PubMed  Google Scholar 

  91. Briggs, D.W., Fisher, J.W. and George, W.J. 1974. Hepatic clearance of intact and desialylated erythropoietin. Am. J. of Physiol. 227: 1385–1388.

    CAS  Google Scholar 

  92. Fukuda, M.N., Saski, H., Lopez, L. and Fukuda, M. 1989. Survival of recombinant erythropoietin in the circulation: the role of carbohydrates. Blood 73: 84–89.

    CAS  PubMed  Google Scholar 

  93. Weiss, P. and Ashwell, G. 1989. The asialoglycoprotein receptor: properties and modulation by ligand. Prog. Clin. Biol. Res. 300: 169–184.

    CAS  PubMed  Google Scholar 

  94. Donahue, R.E., Wang, E.A., Kaufman, R.J., Foutch, L., Leary, A.C., Witek-Giannetti, J.S., Metzger, M., Hewick, R.M., Steinbrink, D.R., Shaw, G., Kamen, R. and Clark, S.C. 1986. Effects of N-linked carbohydrate on the in vivo properties of human GM-CSF. Cold Spring Harbor Symposia on Quantitative Biology 51: 685–692.

    CAS  PubMed  Google Scholar 

  95. Ezekowitz, R.A.B. and Stahl, P.D. 1988. The structure and function of vertebrate mannose lectin-like proteins. J. Cell. Sci. Suppl. 9: 121–133.

    CAS  PubMed  Google Scholar 

  96. Stahl, P.D. 1990. The macrophage mannose receptor: current status. Am. J. Respir. Cell Mol. Biol. 2: 317–318.

    CAS  PubMed  Google Scholar 

  97. Owensby, D.A., Sobel, B.E. and Schwartz, A.L. 1988. Receptor-mediated endocytosis of tissue-type plasminogen activator by the human hepatoma cell line Hep G2. J. Biol. Chem. 263: 10587–10594.

    CAS  PubMed  Google Scholar 

  98. Tanswell, P., Schluter, M. and Krause, J. 1989. Pharmacokinetics and isolated liver perfusion of carbohydrate modified recombinant tissue-plasminogen activator. Fibrinolysis 3: 79–84.

    CAS  Google Scholar 

  99. Hotchkiss, A., Refino, C.J., Leonard, C.K., O'Connor, J.V., Crowley, C., McCabe, J., Tate, K., Nakamura, G., Powers, D., Levinson, A., Mohler, M. and Spellman, M.W. 1988. The influence of carbohydrate structure on the clearance of recombinant tissue-type plasminogen activator. Thomb. Haem. 60: 255–261.

    CAS  Google Scholar 

  100. Kaniwar, Y.S. 1984. Biology of disease: biophysiology of glomerular filtration and proteinuria. Lab. Invest. 51: 7–21.

    Google Scholar 

  101. Gross, V., Heinrich, P.C., vom Berg, D., Steube, K., Andus, T., Tran-Thi, T.-A., Decker, K. and Gerok, W. 1988. Involvement of various organs in the initial plasma clearance of differently glycosylated rat liver secretory proteins. Eur. J. Biochem. 173: 653–659.

    CAS  PubMed  Google Scholar 

  102. Gross, V., Steube, K., Tran-Thi, T.-A., Gerok, W. and Heinrich, P.C. 1989. Role of N-glycosylation for the plasma clearance of rat liver secretory glycoproteins. Biochem. Soc. Trans.:17: 21–23.

    CAS  PubMed  Google Scholar 

  103. Schifferli, J.A., Ng, Y.C. and Peter, D.K. 1986. The role of complement and its receptor in the elimination of immune complexes. New Eng. J. Med. 315: 488–495.

    CAS  PubMed  Google Scholar 

  104. Anderson, C.L. 1989. Human IgG Fc receptors. Clin. Immunol. Immunopath. 53: S63–S71.

    CAS  Google Scholar 

  105. Baatrup, G. 1989. Immune complex modulation by plasma proteins. With special reference to the complement system and autoimmune diseases. Danish. Med. Bull. 36: 443–463.

    CAS  PubMed  Google Scholar 

  106. Vallbracht, A., Treuner, J., Flehmig, B., Joesters, K.-E. and Niethammer, D. 1981. Interferon-neutralizing antibodies in a patient treated with human fibroblast interferon. Nature 289: 496–497.

    CAS  PubMed  Google Scholar 

  107. Quesada, J.R. and Gutterman, J.U. 1983. Clinical study of recombinant DNA-produced leukocyte interferon (clone A) in an intermittent schedule in cancer patients. J. Natl. Cancer Inst. 70: 1041–1046.

    CAS  PubMed  Google Scholar 

  108. Trown, P.W., Kramer, M.J., Dennin, R.A., Connell, E.V., Palleroni, A.V., Quesada, J. and Gutterman, J.U. 1983. Antibodies to human leucocyte interferons in cancer patients. Lancet, 2: 81–87.

    Google Scholar 

  109. Gribben, J.G., Devereux, S., Thomas, N.S.B., Keim, M., Jones, H.M., Goldstone, A.H. and Linch, D.C. 1990. Development of antibodies to unprotected glycosylation sites on recombinant human GM-CSF. Lancet 335: 434–437.

    CAS  PubMed  Google Scholar 

  110. Bendtzen, K., Svenson, M., Jonsson, V. and Hippe, E. 1990. Auto-antibodies to cytokines—friends or foes? Immunol. Today 11: 167–169.

    CAS  PubMed  Google Scholar 

  111. Tanigawara, Y., Hori, R., Okumura, K., Tsuji, J.-i., Shimizu, N., Noma, S., Suzuki, J., Livingston, D.J., Richards, S.M., Keyes, L.D., Couch, R.C. and Erickson, M.K. 1990. Pharmacokinetics in chimpanzees of recombinant human tissue-type plasminogen activator produced mouse C127 and Chinese hamster ovary cells. Chem. Pharm. Bull. 38: 517–522.

    CAS  PubMed  Google Scholar 

  112. Rijken, D.C., Otter, M., Kuiper, J. and van Berkel, T.J.C. 1990. Receptor-mediated endocytosis of tissue-type plasminogen activator (t-PA) by liver cells. Thrombosis Res. Supplement X: 63–71.

    Google Scholar 

  113. Krause, J., Seydel, W., Heinzel, G. and Tanswell, P. 1990. Different receptors mediate the hepatic catabolism of tissue-type plasminogen activator and urokinase. Biochem. J. 267: 647–652.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Spik, G., Debruyne, V., Montreuil, J., van Halbeek, H. and Vliegenthart, J.F.C. 1985. Primary structure of two sialylated triantennary glycans from human serotransferrin. FEBS Lett. 183: 65–69.

    CAS  PubMed  Google Scholar 

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Goochee, C., Gramer, M., Andersen, D. et al. The Oligosaccharides of Glycoproteins: Bioprocess Factors Affecting Oligosaccharide Structure and their Effect on Glycoprotein Properties. Nat Biotechnol 9, 1347–1355 (1991). https://doi.org/10.1038/nbt1291-1347

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