Browse > Article

Glyco-engineering of Biotherapeutic Proteins in Plants  

Ko, Kisung (Department of Biological Science, College of Natural Sciences, Wonkwang University)
Ahn, Mi-Hyun (Department of Biological Science, College of Natural Sciences, Wonkwang University)
Song, Mira (Department of Biological Science, College of Natural Sciences, Wonkwang University)
Choo, Young-Kug (Department of Biological Science, College of Natural Sciences, Wonkwang University)
Kim, Hyun Soon (Plant Cell Biotechnology Lab., Korea Research Institute of Bioscience and Biotechnology)
Ko, Kinarm (Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology)
Joung, Hyouk (Plant Cell Biotechnology Lab., Korea Research Institute of Bioscience and Biotechnology)
Publication Information
Molecules and Cells / v.25, no.4, 2008 , pp. 494-503 More about this Journal
Abstract
Many therapeutic glycoproteins have been successfully generated in plants. Plants have advantages regarding practical and economic concerns, and safety of protein production over other existing systems. However, plants are not ideal expression systems for the production of biopharmaceutical proteins, due to the fact that they are incapable of the authentic human N-glycosylation process. The majority of therapeutic proteins are glycoproteins which harbor N-glycans, which are often essential for their stability, folding, and biological activity. Thus, several glyco-engineering strategies have emerged for the tailor-making of N-glycosylation in plants, including glycoprotein subcellular targeting, the inhibition of plant specific glycosyltranferases, or the addition of human specific glycosyltransferases. This article focuses on plant N-glycosylation structure, glycosylation variation in plant cell, plant expression system of glycoproteins, and impact of glycosylation on immunological function. Furthermore, plant glyco-engineering techniques currently being developed to overcome the limitations of plant expression systems in the production of therapeutic glycoproteins will be discussed in this review.
Keywords
Glycoprotein; Glycosylation; Molecular Biopharming; Monoclonal Antibody; Recombinant Protein; Transgenic Plant;
Citations & Related Records
Times Cited By KSCI : 3  (Citation Analysis)
Times Cited By Web Of Science : 15  (Related Records In Web of Science)
연도 인용수 순위
1 AS Insights (2005). Monoclonal antibody therapeutics-current market dynamics & future outlook. pp. 42
2 Bardor, M., Cabrera, G., Rudd, P.M., Dwek, R.A., Cremata, J.A., and Lerouge, P. (2006). Analytical strategies to investigate plant N-glycan profiles in the context of plant-made pharmaceuticals. Curr. Opin. Struct. Biol. 16, 576-583   DOI   ScienceOn
3 Hiatt, A., Cafferkey, R., and Bowdish, K. (1989). Production of antibodies in transgenic plants. Nature 342, 76-78   DOI   ScienceOn
4 Jobling, S.A., Jarman, C., Teh, M.M., Holmberg, N., Blake, C., and Verhoeyen, M.E. (2003). Immunomodulation of enzyme function in plants by single-domain antibody fragments. Nat. Biotechnol. 21, 77-80   DOI   ScienceOn
5 Ko, K., Tekoah, Y., Rudd, P.M., Harvey, D.J., Dwek, R.A., Spitsin, S., Hanlon, C.A., Rupprecht, C., Dietzschold, B., Golovkin, M., et al. (2003). Function and glycosylation of plant-derived antiviral monoclonal antibody. Proc. Natl. Acad. Sci. USA 100, 8013-8018
6 Ko, K., Steplewski, Z., Glogowska, M., and Koprowski, H. (2005). Inhibition of tumor growth by plant-derived mAb. Proc. Natl. Acad. Sci. USA 102, 7026-7030
7 Niwa, R., Hatanaka, S., Shoji-Hosaka, E., Sakurada, M., Kobayashi, Y., Uehara, A., Yokoi, H., Nakamura, K., and Shitara, K. (2004). Enhancement of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 Is independent of Fcgamma RIIIa functional polymorphism. Clin. Cancer Res. 10, 6248-6255   DOI   ScienceOn
8 Rudd, P.M., Wormald, M.R., and Dwek, R.A. (2004). Sugar-mediated ligand-receptor interactions in the immune system. Trends Biotechnol. 22, 524-530   DOI   ScienceOn
9 Shah, N., Kuntz, D.A., and Rose, D.R. (2003). Comparison of kifunensine and 1-deoxymannojirimycin binding to class I and II alpha-mannosidases demonstrates different saccharide distortions in inverting and retaining catalytic mechanisms. Biochemistry 42, 13812-13816   DOI   ScienceOn
10 Shields, R.L., Lai, J., Keck, R., O'Connell, L.Y., Hong, K., Meng, Y.G., Weikert, S.H., and Presta, L.G. (2002). Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J. Biol. Chem. 277, 26733-26740   DOI   ScienceOn
11 Shin, D.J., Kang, J.Y., Kim, Y.U., Yoon, J.S., Choy, H.E., Maeda, Y., Kinoshita, T., and Hong, Y. (2006). Isolation of new CHO cell mutants defective in CMP-Sialic Acid biosynthesis and transport. Mol. Cells 22, 343-352
12 Shinkawa, T., Nakamura, K., Yamane, N., Shoji-Hosaka, E., Kanda, Y., Sakurada, M., Uchida, K., Anazawa, H., Satoh, M., Yamasaki, M., 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, 3466-3473   DOI   ScienceOn
13 Walker, M.R., Lund, J., Thompson, K.M., and Jefferis, R. (1989). A glycosylation of human IgG1 and IgG3 monoclonal antibodies can eliminate recognition by human cells expressing Fc gamma RI and/or Fc gamma RII receptors. Biochem. J. 259, 347-353   DOI
14 Wee, E.G., Sherrier, D.J., Prime, T.A., and Dupree, P. (1998). Targeting of active sialyltransferase to the plant Golgi apparatus. Plant Cell 10, 1759-1768   DOI   ScienceOn
15 Zeleny, R., Kolarich, D., Strasser, R., and Altmann, F. (2006a). Sialic acid concentrations in plants are in the range of inadvertent contamination. Planta 224, 222-227   DOI   ScienceOn
16 Freeze, H.H., and Aebi, M. (2005). Altered glycan structures: the molecular basis of congenital disorders of glycosylation. Curr. Opin. Struct. Biol. 15, 490-498   DOI   ScienceOn
17 Zeleny, R., Leonard, R., Dorfner, G., Dalik, T., Kolarich, D., and Altmann, F. (2006b). Molecular cloning and characterization of a plant alpha1, 3/4-fucosidase based on sequence tags from almond fucosidase I. Phytochemistry 67, 641-648   DOI   ScienceOn
18 Bakker, H., Schijlen, E., de Vries, T., Schiphorst, W.E., Jordi, W., Lommen, A., Bosch, D., and van Die, I. (2001b). Plant members of the alpha1 ${\to}$ 3/4-fucosyltransferase gene family encode an alpha1 ${\to}$ 4-fucosyltransferase, potentially involved in Lewis (a) biosynthesis, and two core alpha1 ${\to}$ 3-fucosyltransferases. FEBS Lett. 507, 307-312   DOI   ScienceOn
19 Deisenhofer, J. (1981). Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-A resolution. Biochemistry 20, 2361-2370   DOI   ScienceOn
20 Faye, L., Gomord, V., Fitchette-Lainé, A.C., and Chrispeels, M.J. (1993). Affinity purification of antibodies specific for Asnlinked glycans containing alpha 1 ${\to}$ 3 fucose or beta 1 ${\to}$ 2 xylose. Anal. Biochem. 209, 104-108   DOI   ScienceOn
21 Kim, S.M., Lee, J.S., Lee, Y.H., Kim, W.J., Do, S.I., Choo, Y.K., and Park, Y.I. (2007). Increased ${\alpha}$(2,3)-Sialylation and hyperglycosylation of N-glycans in embryonic rat cortical neurons during Camptothecin-induced apoptosis. Mol. Cells 24, 416-423
22 Paccalet, T., Bardor, M., Rihouey, C., Delmas, F., Chevalier, C., D'Aoust, M.A., Faye, L., Vézina, L., Gomord, V., and Lerouge, P. (2007). Engineering of a sialic acid synthesis pathway in transgenic plants by expression of bacterial Neu5Ac-synthesizing enzymes. Plant Biotechnol. J. 5, 16-25   DOI   ScienceOn
23 van Ree, R., Cabanes-Macheteau, M., Akkerdaas, J., Milazzo, J.P., Loutelier-Bourhis, C., Rayon, C., Villalba, M., Koppelman, S., Aalberse, R., Rodriguez, R., et al. (2000). Beta(1,2)-xylose and alpha(1,3)-fucose residues have a strong contribution in IgE binding to plant glycoallergens. J. Biol. Chem. 275, 11451-11458   DOI   ScienceOn
24 Perlman, S., van den Hazel, B., Christiansen, J., Gram-Nielsen, S., Jeppesen, C.B., Andersen, K.V., Halkier, T., Okkels, S., and Schambye, H.T. (2003). Glycosylation of an N-terminal extension prolongs the half-life and increases the in vivo activity of follicle stimulating hormone. J. Clin. Endocrinol. Metab. 88, 3227-3235   DOI   ScienceOn
25 Wide, L. (1986). The regulation of metabolic clearance rate of human FSH in mice by variation of the molecular structure of the hormone. Acta Endocrinologica 112, 519-529
26 Mayfield, S.P., Franklin, S.E., and Lerner, R.A. (2003). Expression and assembly of a fully active antibody in algae. Proc. Natl. Acad. Sci. USA 100, 438-442
27 Schahs, M., Strasser, R., Stadlmann, J., Kunert, R., Rademacher, T., and Steinkellner, H. (2007). Production of a monoclonal antibody in plants with a humanized N-glycosylation pattern. Plant Biotechnol. J. 5, 657-663   DOI   ScienceOn
28 Fitchette-Lainé, A.C., Gomord, V., Cabanes, M., Michalski, J.C., Saint Macary, M., Foucher, B., Cavelier, B., Hawes, C., Lerouge, P., and Faye, L. (1997). N-glycans harboring the Lewis a epitope are expressed at the surface of plant cells. Plant J. 12, 1411-1417   DOI   ScienceOn
29 Gomord, V., Chamberlain, P., Jefferis, R., and Faye, L. (2005). Biopharmaceutical production in plants: problems, solutions and opportunities. Trends Biotechnol. 23, 559-565   DOI   ScienceOn
30 Pagny, S., Cabanes-Macheteau, M., Gillikin, J.W., Leborgne- Castel, N., Lerouge, P., Boston, R.S., Faye, L., and Gomord, V. (2000). Protein recycling from the Golgi apparatus to the endoplasmic reticulum in plants and its minor contribution to calreticulin retention. Plant Cell 12, 739-756   DOI   ScienceOn
31 Sharp, J.M., and Doran, P.M. (2001). Characterization of monoclonal antibody fragments produced by plant cells. Biotechnol. Bioeng. 73, 338-346   DOI   ScienceOn
32 Faye, L., Boulaflous, A., Benchabane, M., Gomord, V., and Michaud, D. (2005). Protein modifications in the plant secretory pathway: current status and practical implications in molecular pharming. Vaccine 23, 1770-1778   DOI   ScienceOn
33 Koprowski, H., and Croce, C. (1980). Hybridomas revisited. Science 210, 248   DOI
34 Okazaki, A., Shoji-Hosaka, E., Nakamura, K., Wakitani, M., Uchida, K., Kakita, S., Tsumoto, K., Kumagai, I., and Shitara, K. (2004). Fucose depletion from human IgG1 oligosaccharide enhances binding enthalpy and association rate between IgG1 and FcgammaRIIIa. J. Mol. Biol. 336, 1239-1249   DOI   ScienceOn
35 Misaki, R., Fujiyama, K., and Seki, T. (2006). Expression of human CMP-N-acetylneuraminic acid synthetase and CMP-sialic acid transporter in tobacco suspension-cultured cell. Biochem. Biophys. Res. Commun. 339, 1184-1189   DOI   ScienceOn
36 Tekoah, Y., Ko, K., Koprowski, H., Harvey, D.J., Wormald, M.R., Dwek, R.A., and Rudd, P.M. (2004). Controlled glycosylation of therapeutic antibodies in plants. Arch. Biochem. Biophys. 426, 266-278   DOI   ScienceOn
37 Cabanes-Macheteau, M., Fitchette-Lainé, A.C., Loutelier-Bourhis, C., Lange, C., Vine, N.D., Ma, J.K., Lerouge, P., and Faye, L. (1999). N-glycosylation of a mouse IgG expressed in transgenic tobacco plants. Glycobiology 9, 365-372   DOI
38 Conrad, U., and Fiedler, U. (1998). Compartment-specific accumulation of recombinant immunoglobulins in plant cells: an essential tool for antibody production and immunomodulation of physiological functions and pathogen activity. Plant Mol. Biol. 38, 101-109   DOI
39 Koprivova, A., Stemmer, C., Altmann, F., Hoffmann, A., Kopriva, S., Gorr, G., Reski, R., and Decker, E.L. (2004). Targeted knockouts of Physcomitrella lacking plant specific immunogenic N-glycans. Plant Biotech. J. 2, 517-523   DOI   ScienceOn
40 Petruccelli, S., Otegui, M.S., Lareu, F., Tran Dinh, O., Fitchette, A.C., Circosta, A., Rumbo, M., Bardor, M., Carcamo, R., Gomord, V., et al. (2006). A KDEL-tagged monoclonal antibody is efficiently retained in the endoplasmic reticulum in leaves, but is both partially secreted and sorted to protein storage vacuoles in seeds. Plant Biotechnol. J. 4, 511-527
41 Wenderoth, I., and von Schaewen, A. (2000). Isolation and characterization of plant- N-acetyl glucosaminyltransferase I (GntI) cDNA sequences. Functional analyses in the Arabidopsis cgl mutant and in antisense plants. Plant Physiol. 123, 1097-1108   DOI
42 Ko, K., and Koprowski, H. (2005). Plant biopharming of monoclonal antibodies. Virus Res. 111, 93-100   DOI   ScienceOn
43 Kurosaka, A., Yano, A., Itoh, N., Kuroda, Y., Nakagawa, T., and Kawasaki, T. (1991). The structure of a neural specific carbohydrate epitope of horseradish peroxidase recognized by antihorseradish peroxidase antiserum. J. Biol. Chem. 266, 4168-4172
44 Sriraman, R., Bardor, M., Sack, M., Vaquero, C., Faye, L., Fischer, R., Finnern, R., and Lerouge, P. (2004). Recombinant antihCG antibodies retained in the endoplasmic reticulum of transformed plants lack core-xylose and core-alpha(1,3)-fucose residues. Plant Biotechnol. J. 2, 279-287   DOI   ScienceOn
45 Bakker, H., Bardor, M., Molthoff, J.W., Gomord, V., Elbers, I., Stevens, L.H., Jordi, W., Lommen, A., Faye, L., Lerouge, P., et al. (2001a). Galactose-extended glycans of antibodies produced by transgenic plants. Proc. Natl. Acad. Sci. USA 98, 2899-2904
46 Umana, P., Jean-Mairet, J., and Bailey, J.E. (1999). Tetracycline-regulated overexpression of glycosyltransferases in Chinese hamster ovary cells. Biotechnol. Bioeng. 65, 542-549   DOI   ScienceOn
47 Vitale, A., and Chrispeels, M.J. (1984). Transient N-acetylglucosamine in the biosynthesis of phytohemagglutinin: attachment in the Golgi apparatus and removal in protein bodies. J. Cell Biol. 99(1 Pt 1), 133-140   DOI
48 Wright, K.E., Prior, F., Sardana, R., Altosaar, I., Dudani, A.K., Ganz, P.R., and Tackaberry, E.S. (2001). Sorting of glycoprotein B from human cytomegalovirus to protein storage vesicles in seeds of transgenic tobacco. Transgenic Res. 10, 177-181   DOI   ScienceOn
49 Dorai, H., Mueller, B.M., Reisfeld, R.A., and Gillies, S.D. (1991). Aglycosylated chimeric mouse/human IgG1 antibody retains some effector function. Hybridoma 10, 211-217   DOI
50 Kelm, S., and Schauer, R. (1997). Sialic acids in molecular and cellular interactions. Int. Rev. Cytol. 175, 137-240   DOI   ScienceOn
51 Schouten, A., Roosien, J., van Engelen, F.A., de Jong, G.A., Borst-Vrenssen, A.W., Zilverentant, J.F., Bosch, D., Stiekema, W.J., Gommers, F.J., Schots, A., et al. (1996). The C-terminal KDEL sequence increases the expression level of a single-chain antibody designed to be targeted to both the cytosol and the secretory pathway in transgenic tobacco. Plant Mol. Biol. 30, 781-793   DOI   ScienceOn
52 Brodzik, R., Glogowska, M., Bandurska, K., Okulicz, M., Deka, D., Ko, K., van der Linden, J., Leusen, J.H.W., Pogrebnyak, N., Golovkin, M., et al. (2006). Plant-derived anti-Lewis Y mAb exhibits biological activities for efficient immunotherapy against human cancer cells. Proc. Natl. Acad. Sci. USA 103, 8804-8809
53 Elbers, I.J., Stoopen, G.M., Bakker, H., Stevens, L.H., Bardor, M., Molthoff, J.W., Jordi, W.J., Bosch, D., and Lommen, A. (2001). Influence of growth conditions and developmental stage on Nglycan heterogeneity of transgenic immunoglobulin G and endogenous proteins in tobacco leaves. Plant Physiol. 126, 1314-1322   DOI   ScienceOn
54 Li, L., Yan, J., and Zhao, M.P. (2006). Improvement of the performance of an immunoaffinity extraction method via region-specific immobilization of IgG. J. Chromatogr. A. 1103, 350-355
55 Werner, R.G., Kopp, K., and Schlueter, M. (2007). Glycosylation of therapeutic proteins in different production systems. Acta Paediatr. Suppl. 96, 17-22
56 Fitchette, A.C., Cabanes-Macheteau, M., Marvin, L., Martin, B., Satiat-Jeunemaitre, B., Gomord, V., Crooks, K., Lerouge, P., Faye, L., and Hawes, C. (1999). Biosynthesis and immunolocalization of Lewis a-containing N-glycans in the plant cell. Plant Physiol. 121, 333-344   DOI
57 Wright, A., and Morrison, S.L. (1997). Effect of glycosylation on antibody function: implications for genetic engineering. Trends Biotechnol. 15, 26-32   DOI   ScienceOn
58 Peeters, K., De Wilde, C., and Depicker, A. (2001). Highly efficient targeting and accumulation of a F(ab) fragment within the secretory pathway and apoplast of Arabidopsis thaliana. Eur. J. Biochem. 268, 4251-4260   DOI   ScienceOn
59 Rayon, C., Cabanes-Macheteau, M., Loutelier-Bourhis, C., Salliot-Maire, I., Lemoine, J., Reiter, W.D., Lerouge, P., and Faye, L. (1999). Characterization of N-glycans from Arabi-dopsis. Application to a fucose-deficient mutant. Plant Physiol. 119, 725-734   DOI
60 Faye, L., Sturm, A., Bollini, R., Vitale, A., and Chrispeels, M.J. (1986b). The position of the oligosaccharide side-chains of phytohemaglutinin and their accessibility to glycosidases determines their subsequent processing in the Golgi. Eur. J. Biochem. 158, 655-661   DOI   ScienceOn
61 Kaneko, M., and Nighorn, A. (2003). Interaxonal Eph-ephrin signaling may mediate sorting of olfactory sensory axons in Manduca sexta. J. Neurosci. 23, 11523-11538   DOI
62 Mason, H.S., Lam, D.M., and Arntzen, C.J. (1992). Expression of hepatitis B surface antigen in transgenic plants. Proc. Natl. Acad. Sci. USA 89, 11745-11749
63 Seveno, M., Bardor, M., Paccalet, T., Gomord, V., Lerouge, P., Faye, L. (2004). Glycoprotein sialylation in plants? Nat. Biotechnol. 22, 1351-1352   DOI   ScienceOn
64 Ma, J.K., Hikmat, B.Y., Wycoff, K., Vine, N.D., Chargelegue, D., Yu, L., Hein, M.B., and Lehner, T. (1998). Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat. Med. 4, 601-606   DOI   ScienceOn
65 Helenius, A., and Aebi, M. (2001). Intracellular functions of N-linked glycans. Science 291, 2364-2369   DOI   ScienceOn
66 Kanwar, Y.S., Hascall, V.C., Jakubowski, M.L., and Gibbons, J.T. (1984). Effect of beta-D-xyloside on the glomerular proteoglycans. I. Biochemical studies. J. Cell Biol. 99, 715-722   DOI   ScienceOn
67 Zeitlin, L., Olmsted, S.S., Moench, T.R., Co, M.S., Martinell, B.J., Paradkar, V.M., Russell, D.R., Queen, C., Cone, R.A., and Whaley, K.J. (1998). A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes. Nat. Biotechnol. 16, 1361-1364   DOI   ScienceOn
68 Bardor, M., Loutelier-Bourhis, C., Paccalet, T., Cosette, P., Fitchette, A.C., Vézina, L.P., Trepanier, S., Dargis, M., Lemieux, R., Lange, C., et al. (2003). Monoclonal C5-1 antibody produced in transgenic alfalfa plants exhibits a N-glycosylation that is homogenous and suitable for glyco-engineering into human-compatible structures. Plant Biotechnol. J. 1, 451-462   DOI
69 Chargeleque, D., Vine, N.D., van Dolleweerd, C.J., Drake, P.M.W., and Ma, J.K. (2000). A murine monoclonal antibody produced in transgenic plants with plant-specific glycans is not immunogenic in mice. Transgenic Res. 9, 187-194   DOI   ScienceOn
70 Gomord, V., Sourrouille, C., Fitchette, A.C., Bardor, M., Pagny, S., Lerouge, P., and Faye, L. (2004). Production and glycosylation of plant-made pharmaceuticals: the antibodies as a challenge. Plant Biotechnol. J. 2, 83-100   DOI   ScienceOn
71 Ma, J.K., Drake, P.M., and Christou, P. (2003). The production of recombinant pharmaceutical proteins in plants. Nat. Rev. Genet. 4, 794-805   DOI   ScienceOn
72 Faye, L., Johnson, K.D., and Chrispeels, M.J. (1986a). Oligosaccharide side chains of glycoproteins that remain in the high-mannose form are not accessible to glycosidases. Plant Physiol. 81, 206-211   DOI   ScienceOn
73 Gomord, V., and Faye, L. (2004). Posttranslational modification of therapeutic protein in plants. Curr. Opin. Plant Biol. 7, 171-181   DOI   ScienceOn