Abstract
Like animal cells, plant cells bear mechanisms for protein synthesis and posttranslational modification (glycosylation and phosphorylation) that allow them to be seriously considered as factories for therapeutic proteins, including antibodies, with the development of biotechnology. The plant platform for monoclonal antibody production is an attractive approach due to its flexibility, speed, scalability, low cost of production, and lack of contamination risk from animal-derived pathogens. Contemporary production approaches for therapeutic proteins rely on transgenic plants that are obtained via the stable transformation of plant cells as well as the transient (temporary) expression of foreign proteins. In this review, we discuss present-day approaches for monoclonal antibody production in plants (MAPP), features of carbohydrate composition, and methods for the humanization of the MAPP carbohydrate profile. MAPPs that have successfully passed preclinical studies and may be promising for use in clinical practice are presented here. Perspectives on using MAPPs are determined by analyzing their economic benefits and production rates, which are especially important in personalized cancer therapy as well as in cases of bioterrorism and pandemics.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- ADCC:
-
antibody-dependent cellular cytotoxicity
- ALG:
-
asparagine-linked glycosylation
- Asn297:
-
asparagine residue at position 297 in IgG heavy chain
- BeYDV:
-
bean yellow dwarf virus
- CH :
-
constant region of immunoglobulin heavy chain
- CL :
-
constant region of immunoglobulin light chain
- CMP-Neu5Ac:
-
CMP-acetylneuraminic acid
- CPMV:
-
cowpea mosaic virus
- EGFR:
-
epidermal growth factor receptor
- ER:
-
endoplasmic reticulum
- EV:
-
Ebola virus
- Fab:
-
fragment antigen binding
- Fc:
-
fragment crystallizable
- Fuc:
-
fucose
- FUT11,12:
-
α1,3-fucosyl transferase 11 and 12
- FUT13:
-
α1,4-fucosyl transferase 13
- Fv:
-
fragment variable
- GalT:
-
β1,4-galactosyltransferase
- GALT1:
-
β1,3-galactosyltransferase
- Glc:
-
glucose
- GlcNAc:
-
N-acetylglucosamine
- GNT I:
-
α1,3-mannosyl-glycoprotein 2β-N-acetylglucosamine transferase
- GNT II:
-
α1,6-mannosyl-glycoprotein 2β-N-acetylglucosamine transferase
- GNT III:
-
β1,4-N-acetylglucosamine transferase III
- HIV:
-
human immunodeficiency virus
- Ig:
-
immunoglobulin
- IgG:
-
class G immunoglobulin
- JV:
-
Junin virus
- Man:
-
mannose
- MAPP:
-
monoclonal antibodies produced in plants
- MNS:
-
mannosidase
- Neu5Ac:
-
N-acetylneuraminic acid
- NHL:
-
non-Hodgkin lymphoma
- OST:
-
oligosaccharyltransferase
- PA:
-
Bacillus anthracis protective antigen
- P2G12:
-
TMA 2G12 produced in tobacco plant
- PVX:
-
potato virus X
- rituximab-P:
-
plant-produced TMA rituximab
- RSV:
-
respiratory syncytial virus
- scFv:
-
single-chain variable fragment (fusion protein consisting of VL and VH connected with linker peptide)
- sIgA:
-
secretory IgA
- TMA:
-
therapeutic monoclonal antibodies produced in animal cells
- TMV:
-
tobacco mosaic virus
- trastuzumab-P:
-
plant-produced TMA trastuzumab
- VH :
-
variable region of Ig heavy chain
- VL :
-
variable region of Ig light chain
- WNV:
-
West Nile virus
- 2G12:
-
TMA interacting with GP120 HIV
References
Niwa, R., and Satoh, M. (2015) The current status and prospects of antibody engineering for therapeutic use: focus on glycoengineering technology, J. Pharm. Sci., 104, 930–941.
Arntzen, C. (2015) Plant-made pharmaceuticals: from “Edible Vaccines” to Ebola therapeutics, Plant Biotechnol. J., 13, 1013–1016.
Holtz, B. R., Berquist, B. R., Bennett, L. D., Kommineni, V. J. M., Munigunti, R. K., White, E. L., Wilkerson, D. C., Wong, K.-Y. I., Ly, L. H., and Marcel, S. (2015) Commercial-scale biotherapeutics manufacturing facility for plant-made pharmaceuticals, Plant Biotechnol. J., 13, 1180–1190.
Whaley, K. J., Morton, J., Hume, S., Hiatt, E., Bratcher, B., Klimyuk, V., Hiatt, A., Pauly, M., and Zeitlin, L. (2014) Emerging antibody-based products, Curr. Top. Microbiol. Immunol., 375, 107–126.
Stoger, E., Sack, M., Nicholson, L., Fischer, R., and Christou, P. (2005) Recent progress in plantibody technology, Curr. Pharm. Des., 11, 2439–2457.
Hiatt, A., Cafferkey, R., and Bowdish, K. (1989) Production of antibodies in transgenic plants, Nature, 342, 76–78.
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.
De Muynck, B., Navarre, C., and Boutry, M. (2010) Production of antibodies in plants: status after twenty years, Plant Biotechnol. J., 8, 529–563.
Gleba, Y. Y., Tuse, D., and Giritch, A. (2014) Plant viral vectors for delivery by Agrobacterium, Curr. Top. Microbiol. Immunol., 375, 155–192.
Komarova, T. V., Baschieri, S., Donini, M., Marusic, C., Benvenuto, E., and Dorokhov, Y. L. (2010) Transient expression systems for plant-derived biopharmaceuticals, Expert Rev. Vaccines, 9, 859–876.
Hiatt, A., Whaley, K. J., and Zeitlin, L. (2014) Plantderived monoclonal antibodies for prevention and treatment of infectious disease, Microbiol. Spectr., 2, AID-0004-2012.
Takeyama, N., Kiyono, H., and Yuki, Y. (2015) Plant-based vaccines for animals and humans: recent advances in technology and clinical trials, Ther. Adv. Vaccines, 3, 139–154.
Tschofen, M., Knopp, D., Hood, E., and Stoger, E. (2016) Plant molecular farming: much more than medicines, Annu. Rev. Anal. Chem. (Palo Alto Calif.), 9, 271–294.
Chilton, M.-D. (2001) Agrobacterium. A memoir, Plant Physiol., 125, 9–14.
Marton, L., Wullems, G. J., Molendijk, L., and Schilperoort, R. A. (1979) In vitro transformation of cultured cells from Nicotiana tabacum by Agrobacterium tumefaciens, Nature, 277, 129–131.
Klein, T. M., Wolf, E. D., Wu, R., and Sanford, J. C. (1987) High-velocity microprojectiles for delivering nucleic acids into living cells, Nature, 327, 70–73.
De Muynck, B., Navarre, C., and Boutry, M. (2010) Production of antibodies in plants: status after twenty years, Plant Biotechnol. J., 8, 529–563.
De Wilde, C., De Neve, M., De Rycke, R., Bruyns, A. M., De Jaeger, G., Van Montagu, M., Depicker, A., and Engler, G. (1996) Intact antigen-binding MAK33 antibody and Fab fragment accumulate in intercellular spaces of Arabidopsis thaliana, Plant Sci., 114, 233–241.
Ma, J. K., Hiatt, A., Hein, M., Vine, N. D., Wang, F., Stabila, P., Van Dolleweerd, C., Mostov, K., and Lehner, T. (1995) Generation and assembly of secretory antibodies in plants, Science, 268, 716–719.
Stoger, E., Fischer, R., Moloney, M., and Ma, J. K.-C. (2014) Plant molecular pharming for the treatment of chronic and infectious diseases, Annu. Rev. Plant Biol., 65, 743–768.
Vamvaka, E., Twyman, R. M., Murad, A. M., Melnik, S., Teh, A. Y.-H., Arcalis, E., Altmann, F., Stoger, E., Rech, E., Ma, J. K. C., Christou, P., and Capell, T. (2016) Rice endosperm produces an underglycosylated and potent form of the HIV-neutralizing monoclonal antibody 2G12, Plant Biotechnol. J., 14, 97–108.
Bock, R. (2015) Engineering plastid genomes: methods, tools, and applications in basic research and biotechnology, Annu. Rev. Plant Biol., 66, 211–241.
Yusibov, V., Kushnir, N., and Streatfield, S. J. (2016) Antibody production in plants and green algae, Annu. Rev. Plant Biol., 67, 669–701.
Rasala, B. A., and Mayfield, S. P. (2015) Photosynthetic biomanufacturing in green algae; production of recombinant proteins for industrial, nutritional, and medical uses, Photosynth. Res., 123, 227–239.
Goodin, M. M., Zaitlin, D., Naidu, R. A., and Lommel, S. A. (2008) Nicotiana benthamiana: its history and future as a model for plant-pathogen interactions, Mol. Plant Microbe Interact., 21, 1015–1026.
Bevan, M. (1984) Binary Agrobacterium vectors for plant transformation, Nucleic Acids Res., 12, 8711–8721.
Lam, E. (1994) Analysis of tissue-specific elements in the CaMV 35S promoter, Results Probl. Cell Differ., 20, 181–196.
Giritch, A., Marillonnet, S., Engler, C., Van Eldik, G., Botterman, J., Klimyuk, V., and Gleba, Y. (2006) Rapid high-yield expression of full-size IgG antibodies in plants coinfected with noncompeting viral vectors, Proc. Natl. Acad. Sci. USA, 103, 14701–14706.
Garabagi, F., McLean, M. D., and Hall, J. C. (2012) Transient and stable expression of antibodies in Nicotiana species, Methods Mol. Biol., 907, 389–408.
Komarova, T. V., Kosorukov, V. S., Frolova, O. Y., Petrunia, I. V., Skrypnik, K. A., Gleba, Y. Y., and Dorokhov, Y. L. (2011) Plant-made trastuzumab (Herceptin) inhibits HER2/Neu+ cell proliferation and retards tumor growth, PLoS One, 6, e17541.
Hamorsky, K. T., Grooms-Williams, T. W., Husk, A. S., Bennett, L. J., Palmer, K. E., and Matoba, N. (2013) Efficient single tobamoviral vector-based bioproduction of broadly neutralizing anti-HIV-1 monoclonal antibody VRC01 in Nicotiana benthamiana plants and utility of VRC01 in combination microbicides, Antimicrob. Agents Chemother., 57, 2076–2086.
Marillonnet, S., Thoeringer, C., Kandzia, R., Klimyuk, V., and Gleba, Y. (2005) Systemic Agrobacterium tumefaciensmediated transfection of viral replicons for efficient transient expression in plants, Nat. Biotechnol., 23, 718–723.
Zhang, B., Rapolu, M., Huang, L., and Su, W. W. (2011) Coordinate expression of multiple proteins in plant cells by exploiting endogenous kex2p-like protease activity, Plant Biotechnol. J., 9, 970–981.
Sainsbury, F., Lavoie, P.-O., D’ Aoust, M.-A., Vezina, L.-P., and Lomonossoff, G. P. (2008) Expression of multiple proteins using full-length and deleted versions of cowpea mosaic virus RNA-2, Plant Biotechnol. J., 6, 82–92.
Diamos, A. G., Rosenthal, S. H., and Mason, H. S. (2016) 5'and 3'-untranslated regions strongly enhance performance of gemini viral replicons in Nicotiana benthamiana leaves, Front. Plant Sci., 7, 200.
Huang, Z., Phoolcharoen, W., Lai, H., Piensook, K., Cardineau, G., Zeitlin, L., Whaley, K. J., Arntzen, C. J., Mason, H. S., and Chen, Q. (2010) High-level rapid production of full-size monoclonal antibodies in plants by a single-vector DNA replicon system, Biotechnol. Bioeng., 106, 9–17.
Esfandiari, N., Arzanani, M. K., Soleimani, M., KohiHabibi, M., and Svendsen, W. E. (2016) A new application of plant virus nanoparticles as drug delivery in breast cancer, Tumour Biol., 37, 1229–1236.
Hehle, V. K., Paul, M. J., Roberts, V. A., Van Dolleweerd, C. J., and Ma, J. K.-C. (2016) Site-targeted mutagenesis for stabilization of recombinant monoclonal antibody expressed in tobacco (Nicotiana tabacum) plants, FASEB J., 30, 1590–1598.
Xu, C., and Ng, D. T. W. (2015) Glycosylation-directed quality control of protein folding, Nat. Rev. Mol. Cell Biol., 16, 742–752.
Nguema-Ona, E., Vicre-Gibouin, M., Gotte, M., Plancot, B., Lerouge, P., Bardor, M., and Driouich, A. (2014) Cell wall O-glycoproteins and N-glycoproteins: aspects of biosynthesis and function, Front. Plant Sci., 5, 499.
Olszewski, N. E., West, C. M., Sassi, S. O., and Hartweck, L. M. (2010) O-GlcNAc protein modification in plants: evolution and function, Biochim. Biophys. Acta, 1800, 49–56.
Strasser, R. (2014) Biological significance of complex Nglycans in plants and their impact on plant physiology, Front. Plant Sci., 5, 363.
Strasser, R. (2016) Plant protein glycosylation, Glycobiology, pii: cww023.
Strasser, R., Altmann, F., and Steinkellner, H. (2014) Controlled glycosylation of plant-produced recombinant proteins, Curr. Opin. Biotechnol., 30, 95–100.
Beck, A., Wagner-Rousset, E., Ayoub, D., Van Dorsselaer, A., and Sanglier-Cianferani, S. (2013) Characterization of therapeutic antibodies and related products, Anal. Chem., 85, 715–736.
Gomord, V., Fitchette, A.-C., Menu-Bouaouiche, L., Saint- Jore-Dupas, C., Plasson, C., Michaud, D., and Faye, L. (2010) Plant-specific glycosylation patterns in the context of therapeutic protein production, Plant Biotechnol. J., 8, 564–587.
Lerouge, P., Cabanes-Macheteau, M., Rayon, C., Fischette-Laine, A. C., Gomord, V., and Faye, L. (1998) N-glycoprotein biosynthesis in plants: recent developments and future trends, Plant Mol. Biol., 38, 31–48.
Veit, C., Vavra, U., and Strasser, R. (2015) N-glycosylation and plant cell growth, Methods Mol. Biol., 1242, 183–194.
Koiwa, H., Li, F., McCully, M. G., Mendoza, I., Koizumi, N., Manabe, Y., Nakagawa, Y., Zhu, J., Rus, A., Pardo, J. M., Bressan, R. A., and Hasegawa, P. M. (2003) The STT3a subunit isoform of the Arabidopsis oligosaccharyl transferase controls adaptive responses to salt/osmotic stress, Plant Cell, 15, 2273–2284.
Lannoo, N., and Van Damme, E. J. M. (2015) Review/Nglycans: the making of a varied toolbox, Plant Sci., 239, 67–83.
Henquet, M., Lehle, L., Schreuder, M., Rouwendal, G., Molthoff, J., Helsper, J., van Der Krol, S., and Bosch, D. (2008) Identification of the gene encoding the alpha1,3mannosyltransferase (ALG3) in Arabidopsis and characterization of downstream N-glycan processing, Plant Cell, 20, 1652–1664.
Hong, Z., Jin, H., Fitchette, A.-C., Xia, Y., Monk, A. M., Faye, L., and Li, J. (2009) Mutations of an alpha1,6 mannosyl transferase inhibit endoplasmic reticulum-associated degradation of defective brassinosteroid receptors in Arabidopsis, Plant Cell, 21, 3792–3802.
Hong, Z., Kajiura, H., Su, W., Jin, H., Kimura, A., Fujiyama, K., and Li, J. (2012) Evolutionarily conserved glycan signal to degrade aberrant brassinosteroid receptors in Arabidopsis, Proc. Natl. Acad. Sci. USA, 109, 11437–11442.
Zhang, M., Henquet, M., Chen, Z., Zhang, H., Zhang, Y., Ren, X., van der Krol, S., Gonneau, M., Bosch, D., and Gong, Z. (2009) LEW3, encoding a putative alpha-1,2mannosyltransferase (ALG11) in N-linked glycoprotein, plays vital roles in cell-wall biosynthesis and the abiotic stress response in Arabidopsis thaliana, Plant J. Cell Mol. Biol., 60, 983–999.
Farid, A., Pabst, M., Schoberer, J., Altmann, F., Glossl, J., and Strasser, R. (2011) Arabidopsis thaliana alpha1,2-glucosyltransferase (ALG10) is required for efficient N-glycosylation and leaf growth, Plant J. Cell Mol. Biol., 68, 314–325.
Liebminger, E., Huttner, S., Vavra, U., Fischl, R., Schoberer, J., Grass, J., Blaukopf, C., Seifert, G. J., Altmann, F., Mach, L., and Strasser, R. (2009) Class I alpha-mannosidases are required for N-glycan processing and root development in Arabidopsis thaliana, Plant Cell, 21, 3850–3867.
Fanata, W. I. D., Lee, K. H., Son, B. H., Yoo, J. Y., Harmoko, R., Ko, K. S., Ramasamy, N. K., Kim, K. H., Oh, D.-B., Jung, H. S., Kim, J.-Y., Lee, S. Y., and Lee, K. O. (2013) N-glycan maturation is crucial for cytokininmediated development and cellulose synthesis in Oryza sativa, Plant J. Cell Mol. Biol., 73, 966–979.
Varki, A., Cummings, R. D., Esko, J. D., Freeze, H. H., Stanley, P., Bertozzi, C. R., Hart, G. W., and Etzler, M. E. (2009) in Essentials of Glycobiology, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.
Strasser, R., Altmann, F., Mach, L., Glossl, J., and Steinkellner, H. (2004) Generation of Arabidopsis thaliana plants with complex N-glycans lacking beta1,2-linked xylose and core alpha1,3-linked fucose, FEBS Lett., 561, 132–136.
Leonard, R., Kolarich, D., Paschinger, K., Altmann, F., and Wilson, I. B. (2004) A genetic and structural analysis of the N-glycosylation capabilities, Plant Mol. Biol., 55, 631–644.
Dicker, M., Tschofen, M., Maresch, D., Konig, J., Juarez, P., Orzaez, D., Altmann, F., Steinkellner, H., and Strasser, R. (2016) Transient glyco-engineering to produce recombinant IgA1 with defined Nand O-glycans in plants, Front. Plant Sci., 7, 18.
Dingjan, T., Spendlove, I., Durrant, L. G., Scott, A. M., Yuriev, E., and Ramsland, P. A. (2015) Structural biology of antibody recognition of carbohydrate epitopes and potential uses for targeted cancer immunotherapies, Mol. Immunol., 67, 75–88.
Strasser, R., Bondili, J. S., Vavra, U., Schoberer, J., Svoboda, B., Glossl, J., Leonard, R., Stadlmann, J., Altmann, F., Steinkellner, H., and Mach, L. (2007) A unique beta1,3-galactosyltransferase is indispensable for the biosynthesis of N-glycans containing Lewis a structures in Arabidopsis thaliana, Plant Cell, 19, 2278–2292.
Roman, V. R. G., Murray, J. C., and Weiner, L. M. (2013) in Antibody Fc: Chap. 1. Antibody-Dependent Cellular Cytotoxicity, Academic Press.
Lindorfer, M. A., Kohl, J., and Taylor, R. P. (2014) in Chap. 3. Interactions Between the Complement System and Fc? Receptors A2 (Nimmerjahn, F., and Ackerman, M. E., eds.) Academic Press, Boston, pp. 49–74.
Gul, N., and Van Egmond, M. (2015) Antibody-dependent phagocytosis of tumor cells by macrophages: a potent effector mechanism of monoclonal antibody therapy of cancer, Cancer Res., 75, 5008–5013.
Nimmerjahn, F. (2014) in Chapter 11. Activating and Inhibitory FcγRs in Autoimmune Disorders, Academic Press, Boston, pp. 195–215.
Strasser, R., Bondili, J. S., Schoberer, J., Svoboda, B., Liebminger, E., Glossl, J., Altmann, F., Steinkellner, H., and Mach, L. (2007) Enzymatic properties and subcellular localization of Arabidopsis beta-N-acetylhexosaminidases, Plant Physiol., 145, 5–16.
Strasser, R., Stadlmann, J., Schahs, M., Stiegler, G., Quendler, H., Mach, L., Glossl, J., Weterings, K., Pabst, M., and Steinkellner, H. (2008) Generation of glyco-engineered Nicotiana benthamiana for the production of monoclonal antibodies with a homogeneous human-like N-glycan structure, Plant Biotechnol. J., 6, 392–402.
Strasser, R., Castilho, A., Stadlmann, J., Kunert, R., Quendler, H., Gattinger, P., Jez, J., Rademacher, T., Altmann, F., Mach, L., and Steinkellner, H. (2009) Improved virus neutralization by plant-produced antiHIV antibodies with a homogeneous beta1,4-galactosylated N-glycan profile, J. Biol. Chem., 284, 20479–20485.
Strasser, R., Stadlmann, J., Schahs, M., Stiegler, G., Quendler, H., Mach, L., Glossl, J., Weterings, K., Pabst, M., and Steinkellner, H. (2008) Generation of glycoengineered Nicotiana benthamiana for the production of monoclonal antibodies with a homogeneous humanlike N-glycan structure, Plant Biotechnol. J., 6, 392–402.
Bardor, M., Faveeuw, C., Fitchette, A.-C., Gilbert, D., Galas, L., Trottein, F., Faye, L., and Lerouge, P. (2003) Immunoreactivity in mammals of two typical plant glycoepitopes, core a(1,3)-fucose and core xylose, Glycobiology, 13, 427–434.
Chargelegue, D., Vine, N. D., Van Dolleweerd, C. J., Drake, P. M., 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.
Jin, C., Altmann, F., Strasser, R., Mach, L., Schahs, M., Kunert, R., Rademacher, T., Glossl, J., and Steinkellner, H. (2008) A plant-derived human monoclonal antibody induces an anti-carbohydrate immune response in rabbits, Glycobiology, 18, 235–241.
Tuse, D., Ku, N., Bendandi, M., Becerra, C., Collins, R., Langford, N., Sancho, S. I., Lopez-Diaz de Cerio, A., Pastor, F., Kandzia, R., Thieme, F., Jarczowski, F., Krause, D., Ma, J. K.-C., Pandya, S., Klimyuk, V., Gleba, Y., and Butler-Ransohoff, J. E. (2015) Clinical safety and immunogenicity of tumor-targeted, plant-made Id-KLH conjugate vaccines for follicular lymphoma, BioMed Res. Int., 648143.
Bosch, D., Castilho, A., Loos, A., Schots, A., and Steinkellner, H. (2013) N-glycosylation of plant-produced recombinant proteins, Curr. Pharm. Des., 19, 5503–5512.
Ferrara, C., Brunker, P., Suter, T., Moser, S., Puntener, U., and Umana, P. (2006) Modulation of therapeutic antibody effector functions by glycosylation engineering: influence of Golgi enzyme localization domain and co-expression of heterologous beta1, 4-N-acetylglucosaminyltransferase III and Golgi alpha-mannosidase II,Biotechnol. Bioeng., 93, 851–861.
Jefferis, R. (2009) Glycosylation as a strategy to improve antibody-based therapeutics, Nat. Rev. Drug Discov., 8, 226–234.
Zeitlin, L., Pettitt, J., Scully, C., Bohorova, N., Kim, D., Pauly, M., Hiatt, A., Ngo, L., Steinkellner, H., Whaley, K. J., and Olinger, G. G. (2011) Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant, Proc. Natl. Acad. Sci. USA, 108, 20690–20694.
Sriraman, R., Bardor, M., Sack, M., Vaquero, C., Faye, L., Fischer, R., Finnern, R., and Lerouge, P. (2004) Recombinant anti-hCG 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.
Triguero, A., Cabrera, G., Cremata, J. A., Yuen, C.-T., Wheeler, J., and Ramirez, N. I. (2005) Plant-derived mouse IgG monoclonal antibody fused to KDEL endoplasmic reticulum-retention signal is N-glycosylated homogeneously throughout the plant with mostly highmannose-type N-glycans, Plant Biotechnol. J., 3, 449–457.
Petruccelli, S., Otegui, M. S., Lareu, F., Tran Dinh, O., Fitchette, A.-C., Circosta, A., Rumbo, M., Bardor, M., Carcamo, R., Gomord, V., and Beachy, R. N. (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.
Loos, A., and Castilho, A. (2015) Transient glyco-engineering of N. benthamiana aiming at the synthesis of multiantennary sialylated proteins, Methods Mol. Biol., 1321, 233–248.
Nagels, B., Van Damme, E. J. M., Pabst, M., Callewaert, N., and Weterings, K. (2011) Production of complex multiantennary N-glycans in Nicotiana benthamiana plants, Plant Physiol., 155, 1103–1112.
Forthal, D. N., Gach, J. S., Landucci, G., Jez, J., Strasser, R., Kunert, R., and Steinkellner, H. (2010) Fc-glycosylation influences Fcγ receptor binding and cell-mediated anti-HIV activity of monoclonal antibody 2G12, J. Immunol., 185, 6876–6882.
Castilho, A., Gruber, C., Thader, A., Oostenbrink, C., Pechlaner, M., Steinkellner, H., and Altmann, F. (2015) Processing of complex N-glycans in IgG Fc-region is affected by core fucosylation, mAbs, 7, 863–870.
Matsuo, K., Kagaya, U., Itchoda, N., Tabayashi, N., and Matsumura, T. (2014) Deletion of plant-specific sugar residues in plant N-glycans by repression of GDP-D-mannose 4,6-dehydratase and β-1,2-xylosyltransferase genes, J. Biosci. Bioeng., 118, 448–454.
Frey, A. D., Karg, S. R., and Kallio, P. T. (2009) Expression of rat beta(1,4)-N-acetylglucosaminyltransferase III in Nicotiana tabacum remodels the plant-specific N-glycosylation, Plant Biotechnol. J., 7, 33–48.
Rouwendal, G. J. A., Wuhrer, M., Florack, D. E. A., Koeleman, C. A. M., Deelder, A. M., Bakker, H., Stoopen, G. M., van Die, I., Helsper, J. P. F. G., Hokke, C. H., and Bosch, D. (2007) Efficient introduction of a bisecting GlcNAc residue in tobacco N-glycans by expression of the gene encoding human N-acetylglucosaminyltransferase III, Glycobiology, 17, 334–344.
Houde, D., Peng, Y., Berkowitz, S. A., and Engen, J. R. (2010) Post-translational modifications differentially affect IgG1 conformation and receptor binding, Mol. Cell. Proteomics, 9, 1716–1728.
Mimura, Y., Kelly, R. M., Unwin, L., Albrecht, S., Jefferis, R., Goodall, M., Mizukami, Y., Mimura-Kimura, Y., Matsumoto, T., Ueoka, H., and Rudd, P. M. (2016) Enhanced sialylation of a human chimeric IgG1 variant produced in human and rodent cell lines, J. Immunol. Methods, 428, 30–36.
Zeleny, R., Kolarich, D., Strasser, R., and Altmann, F. (2006) Sialic acid concentrations in plants are in the range of inadvertent contamination, Planta, 224, 222–227.
Castilho, A., Strasser, R., Stadlmann, J., Grass, J., Jez, J., Gattinger, P., Kunert, R., Quendler, H., Pabst, M., Leonard, R., Altmann, F., and Steinkellner, H. (2010) In planta protein sialylation through overexpression of the respective mammalian pathway, J. Biol. Chem., 285, 15923–15930.
Jez, J., Castilho, A., Grass, J., Vorauer-Uhl, K., Sterovsky, T., Altmann, F., and Steinkellner, H. (2013) Expression of functionally active sialylated human erythropoietin in plants, Biotechnol. J., 8, 371–382.
Patel, D., Guo, X., Ng, S., Melchior, M., Balderes, P., Burtrum, D., Persaud, K., Luna, X., Ludwig, D. L., and Kang, X. (2010) IgG isotype, glycosylation, and EGFR expression determine the induction of antibody-dependent cellular cytotoxicity in vitro by cetuximab, Hum. Antibodies, 19, 89–99.
Jarczowski, F., Kandzia, R., Thieme, F., Klimyuk, V., and Gleba, Y. (2016) Methods of modulating N-glycosylation site occupancy of plant-produced glycoproteins and recombinant glycoproteins, United States Patent Application No. 20160115498.
Engelman, A., and Cherepanov, P. (2012) The structural biology of HIV-1: mechanistic and therapeutic insights, Nat. Rev. Microbiol., 10, 279–290.
Morris, G. C., Wiggins, R. C., Woodhall, S. C., Bland, J. M., Taylor, C. R., Jespers, V., Vcelar, B. A., and Lacey, C. J. (2014) MABGEL 1: first phase 1 trial of the anti-HIV-1 monoclonal antibodies 2F5, 4E10 and 2G12 as a vaginal microbicide, PLoS One, 9, e116153.
Rademacher, T., Sack, M., Arcalis, E., Stadlmann, J., Balzer, S., Altmann, F., Quendler, H., Stiegler, G., Kunert, R., Fischer, R., and Stoger, E. (2008) Recombinant antibody 2G12 produced in maize endosperm efficiently neutralizes HIV-1 and contains predominantly single-GlcNAc N-glycans, Plant Biotechnol. J., 6, 189–201.
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.
Ma, J. K.-C., Drossard, J., Lewis, D., Altmann, F., Boyle, J., Christou, P., Cole, T., Dale, P., Van Dolleweerd, C. J., Isitt, V., Katinger, D., Lobedan, M., Mertens, H., Paul, M. J., Rademacher, T., Sack, M., Hundleby, P. A. C., Stiegler, G., Stoger, E., Twyman, R. M., Vcelar, B., and Fischer, R. (2015) Regulatory approval and a first-in-human phase I clinical trial of a monoclonal antibody produced in transgenic tobacco plants, Plant Biotechnol. J., 13, 1106–1120.
Sainsbury, F., Sack, M., Stadlmann, J., Quendler, H., Fischer, R., and Lomonossoff, G. P. (2010) Rapid transient production in plants by replicating and non-replicating vectors yields high quality functional anti-HIV antibody, PLoS One, 5, e13976.
Sainsbury, F., Thuenemann, E. C., and Lomonossoff, G. P. (2009) pEAQ: versatile expression vectors for easy and quick transient expression of heterologous proteins in plants, Plant Biotechnol. J., 7, 682–693.
Paul, M., Reljic, R., Klein, K., Drake, P. M. W., van Dolleweerd, C., Pabst, M., Windwarder, M., Arcalis, E., Stoger, E., Altmann, F., Cosgrove, C., Bartolf, A., Baden, S., and Ma, J. K.-C. (2014) Characterization of a plantproduced recombinant human secretory IgA with broad neutralizing activity against HIV, mAbs, 6, 1585–1597.
Olinger, G. G., Pettitt, J., Kim, D., Working, C., Bohorov, O., Bratcher, B., Hiatt, E., Hume, S. D., Johnson, A. K., Morton, J., Pauly, M., Whaley, K. J., Lear, C. M., Biggins, J. E., Scully, C., Hensley, L., and Zeitlin, L. (2012) Delayed treatment of Ebola virus infection with plantderived monoclonal antibodies provides protection in rhesus macaques, Proc. Natl. Acad. Sci. USA, 109, 18030–18035.
Zeitlin, L., Pettitt, J., Scully, C., Bohorova, N., Kim, D., Pauly, M., Hiatt, A., Ngo, L., Steinkellner, H., Whaley, K. J., and Olinger, G. G. (2011) Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant, Proc. Natl. Acad. Sci. USA, 108, 20690–20694.
Qiu, X., Alimonti, J. B., Melito, P. L., Fernando, L., Stroher, U., and Jones, S. M. (2011) Characterization of Zaire ebolavirus glycoprotein-specific monoclonal antibodies, Clin. Immunol., 141, 218–227.
Qiu, X., Audet, J., Wong, G., Pillet, S., Bello, A., Cabral, T., Strong, J. E., Plummer, F., Corbett, C. R., Alimonti, J. B., and Kobinger, G. P. (2012) Successful treatment of Ebola virus-infected cynomolgus macaques with monoclonal antibodies, Sci. Transl. Med., 4, 138ra81.
Qiu, X., Wong, G., Audet, J., Bello, A., Fernando, L., Alimonti, J. B., Fausther-Bovendo, H., Wei, H., Aviles, J., Hiatt, E., Johnson, A., Morton, J., Swope, K., Bohorov, O., Bohorova, N., Goodman, C., Kim, D., Pauly, M. H., Velasco, J., Pettitt, J., Olinger, G. G., Whaley, K., Xu, B., Strong, J. E., Zeitlin, L., and Kobinger, G. P. (2014) Reversion of advanced Ebola virus disease in nonhuman primates with ZMAPP, Nature, 514, 47–53.
Lyon, G. M., Mehta, A. K., Varkey, J. B., Brantly, K., Plyler, L., McElroy, A. K., Kraft, C. S., Towner, J. S., Spiropoulou, C., Stroher, U., Uyeki, T. M., Ribner, B. S., and Emory Serious Communicable Diseases Unit (2014) Clinical care of two patients with Ebola virus disease in the United States, N. Engl. J. Med., 371, 2402–2409.
McCarthy, M. (2014) US signs contract with ZMAPP maker to accelerate development of the Ebola drug, BMJ, 349, g5488.
Phoolcharoen, W., Bhoo, S. H., Lai, H., Ma, J., Arntzen, C. J., Chen, Q., and Mason, H. S. (2011) Expression of an immunogenic Ebola immune complex in Nicotiana benthamiana, Plant Biotechnol. J., 9, 807–816.
Enria, D. A., Briggiler, A. M., and Sanchez, Z. (2008) Treatment of Argentine hemorrhagic fever, Antiviral Res., 78, 132–139.
Sanchez, A., Pifat, D. Y., Kenyon, R. H., Peters, C. J., McCormick, J. B., and Kiley, M. P. (1989) Junin virus monoclonal antibodies: characterization and cross-reactivity with other arenaviruses, J. Gen. Virol., 70 (Pt. 5), 1125–1132.
Zeitlin, L., Geisbert, J. B., Deer, D. J., Fenton, K. A., Bohorov, O., Bohorova, N., Goodman, C., Kim, D., Hiatt, A., Pauly, M. H., Velasco, J., Whaley, K. J., Altmann, F., Gruber, C., Steinkellner, H., Honko, A. N., Kuehne, A. I., Aman, M. J., Sahandi, S., Enterlein, S., Zhan, X., Enria, D., and Geisbert, T. W. (2016) Monoclonal antibody therapy for Junin virus infection, Proc. Natl. Acad. Sci. USA, 113, 4458–4463.
Zeitlin, L., Bohorov, O., Bohorova, N., Hiatt, A., Kim, D. H., Pauly, M. H., Velasco, J., Whaley, K. J., Barnard, D. L., Bates, J. T., Crowe, J. E., Piedra, P. A., and Gilbert, B. E. (2013) Prophylactic and therapeutic testing of Nicotiana-derived RSV-neutralizing human monoclonal antibodies in the cotton rat model, mAbs, 5, 263–269.
Hiatt, A., Bohorova, N., Bohorov, O., Goodman, C., Kim, D., Pauly, M. H., Velasco, J., Whaley, K. J., Piedra, P. A., Gilbert, B. E., and Zeitlin, L. (2014) Glycan variants of a respiratory syncytial virus antibody with enhanced effector function and in vivo efficacy, Proc. Natl. Acad. Sci. USA, 111, 5992–5997.
Oliphant, T., Engle, M., Nybakken, G. E., Doane, C., Johnson, S., Huang, L., Gorlatov, S., Mehlhop, E., Marri, A., Chung, K. M., Ebel, G. D., Kramer, L. D., Fremont, D. H., and Diamond, M. S. (2005) Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus, Nat. Med., 11, 522–530.
Lai, H., Engle, M., Fuchs, A., Keller, T., Johnson, S., Gorlatov, S., Diamond, M. S., and Chen, Q. (2010) Monoclonal antibody produced in plants efficiently treats West Nile virus infection in mice, Proc. Natl. Acad. Sci. USA, 107, 2419–2424.
He, J., Lai, H., Engle, M., Gorlatov, S., Gruber, C., Steinkellner, H., Diamond, M. S., and Chen, Q. (2014) Generation and analysis of novel plant-derived antibodybased therapeutic molecules against West Nile virus, PLoS One, 9, e93541.
Lai, H., He, J., Hurtado, J., Stahnke, J., Fuchs, A., Mehlhop, E., Gorlatov, S., Loos, A., Diamond, M. S., and Chen, Q. (2014) Structural and functional characterization of an anti-West Nile virus monoclonal antibody and its single-chain variant produced in glycoengineered plants, Plant Biotechnol. J., 12, 1098–1107.
Hull, A. K., Criscuolo, C. J., Mett, V., Groen, H., Steeman, W., Westra, H., Chapman, G., Legutki, B., Baillie, L., and Yusibov, V. (2005) Human-derived, plantproduced monoclonal antibody for the treatment of anthrax, Vaccine, 23, 2082–2086.
Mett, V., Chichester, J. A., Stewart, M. L., Musiychuk, K., Bi, H., Reifsnyder, C. J., Hull, A. K., Albrecht, M. T., Goldman, S., Baillie, L. W. J., and Yusibov, V. (2011) A non-glycosylated, plant-produced human monoclonal antibody against anthrax protective antigen protects mice and non-human primates from B. anthracis spore challenge, Hum. Vaccin., 7 (Suppl.), 183–190.
Almquist, K. C., McLean, M. D., Niu, Y., Byrne, G., Olea-Popelka, F. C., Murrant, C., Barclay, J., and Hall, J. C. (2006) Expression of an anti-botulinum toxin A neutralizing single-chain Fv recombinant antibody in transgenic tobacco, Vaccine, 24, 2079–2086.
Evans, S. S., and Clemmons, A. B. (2015) Obinutuzumab: a novel anti-CD20 monoclonal antibody for chronic lymphocytic leukemia, J. Adv. Pract. Oncol., 6, 370–374.
Grohs, B. M., Niu, Y., Veldhuis, L. J., Trabelsi, S., Garabagi, F., Hassell, J. A., McLean, M. D., and Hall, J. C. (2010) Plant-produced trastuzumab inhibits the growth of HER2 positive cancer cells, J. Agric. Food Chem., 58, 10056–10063.
Kosorukov, V. S., Kosobokova, E. N., Pinyugina, M. V., Sevost’yanova, M. A., Shcherbakov, A. I., Andronova, N. V., Solomko, E. Sh., Sheshukova, E. V., Treshchalina, E. M., and Dorokhov, Yu. L. (2015) Biological activity of recombinant antibodies against HER2 receptor obtained from plants, Ross. Bioter. Zh., 14, 105–112.
McCormick, A. A., Kumagai, M. H., Hanley, K., Turpen, T. H., Hakim, I., Grill, L. K., Tuse, D., Levy, S., and Levy, R. (1999) Rapid production of specific vaccines for lymphoma by expression of the tumor-derived single-chain Fv epitopes in tobacco plants, Proc. Natl. Acad. Sci. USA, 96, 703–708.
McCormick, A. A., Corbo, T. A., Wykoff-Clary, S., Nguyen, L. V., Smith, M. L., Palmer, K. E., and Pogue, G. P. (2006) TMV-peptide fusion vaccines induce cell-mediated immune responses and tumor protection in two murine models, Vaccine, 24, 6414–6423.
Bendandi, M., Marillonnet, S., Kandzia, R., Thieme, F., Nickstadt, A., Herz, S., Frode, R., Inoges, S., Lopez-Diaz de Cerio, A., Soria, E., Villanueva, H., Vancanneyt, G., McCormick, A., Tuse, D., Lenz, J., Butler-Ransohoff, J.-E., Klimyuk, V., and Gleba, Y. (2010) Rapid, high-yield production in plants of individualized idiotype vaccines for non-Hodgkin’s lymphoma, Ann. Oncol., 21, 2420–2427.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © E. V. Sheshukova, T. V. Komarova, Y. L. Dorokhov, 2016, published in Biokhimiya, 2016, Vol. 81, No. 10, pp. 1392–1409.
Rights and permissions
About this article
Cite this article
Sheshukova, E.V., Komarova, T.V. & Dorokhov, Y.L. Plant factories for the production of monoclonal antibodies. Biochemistry Moscow 81, 1118–1135 (2016). https://doi.org/10.1134/S0006297916100102
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0006297916100102