Development of systems for the production of plant-derived biopharmaceuticals

Plants

Volumn 9, Issue 1, 2020, Pages

  Moon, Ki Beom ^a,b   Park, Ji Sun ^a   Park, Youn Il ^b   Song, In Ja ^a   Lee, Hyo Jun ^a   Cho, Hye Sun ^a   Jeon, Jae Heung ^a   Kim, Hyun Soon ^a  

^a Korea Research Institute of Bioscience and Biotechnology (KRIBB)   (South Korea)

^b Chungnam National University   (South Korea)

Author keywords

Expression system; Molecular farming; Plant derived protein; Production system; Recombinant protein

Indexed keywords

EID: 85077303669     PISSN: None     EISSN: 22237747     Source Type: Journal    
DOI: 10.3390/plants9010030     Document Type: Review

References (119)

1. Fischer, R.; Liao, Y.-C.; Hoffmann, K.; Schillberg, S.; Emans, N. Molecular farming of recombinant antibodies in plants. Biol. Chem. 1999, 380, 825–839.
2. Fischer, R.; Drossard, J.; Commandeur, U.; Schillberg, S.; Emans, N. Towards molecular farming in the future: Moving from diagnostic protein and antibody production in microbes to plants. Biotechnol. Appl. Biochem. 1999, 30, 101–108.
3. Fischer, R.; Schillberg, S. Molecular Farming: Plant-Made Pharmaceuticals and Technical Proteins; John Wiley & Sons: Hoboken, NJ, USA, 2004.
4. Stoger, E.; Ma, J.K.; Fischer, R.; Christou, P. Sowing the seeds of success: Pharmaceutical proteins from plants. Curr. Opin. Biotechnol. 2005, 16, 167–173.
5. Ma, J.K.C.; Drake, P.M.; Christou, P. Genetic modification: The production of recombinant pharmaceutical proteins in plants. Nat. Rev. Genet. 2003, 4, 794.
6. Kim, Y.-S.; Kim, B.-G.; Kim, T.-G.; Kang, T.-J.; Yang, M.-S. Expression of a cholera toxin b subunit in transgenic lettuce (lactuca sativa L.) using agrobacterium-mediated transformation system. Plant Cell Tissue Organ Cult. 2006, 87, 203–210.
7. Mohebodini, M.; Jalali-Javaran, M.; Alizadeh, H.; Mahboudi, F.; Yarbakht, M. Agrobacterium-mediated transformation of lettuce (lactuca sativa L.) to express igg-binding protein a and human pro-insulin as a fusion protein. J. Hortic. Sci. Biotechnol. 2014, 89, 719–725.
8. Xu, J.; Dolan, M.C.; Medrano, G.; Cramer, C.L.; Weathers, P.J. Green factory: Plants as bioproduction platforms for recombinant proteins. Biotechnol. Adv. 2012, 30, 1171–1184.
9. Faye, L.; Gomord, V. Success stories in molecular farming—A brief overview. Plant Biotechnol. J. 2010, 8, 525–528.
10. Huang, J.; Nandi, S.; Wu, L.; Yalda, D.; Bartley, G.; Rodriguez, R.; Lonnerdal, B.; Huang, N. Expression of natural antimicrobial human lysozyme in rice grains. Mol. Breed. 2002, 10, 83–94.
11. Nandi, S.; Suzuki, Y.A.; Huang, J.; Yalda, D.; Pham, P.; Wu, L.; Bartley, G.; Huang, N.; Lönnerdal, B. Expression of human lactoferrin in transgenic rice grains for the application in infant formula. Plant Sci. 2002, 163, 713–722.
12. Abiri, R.; Valdiani, A.; Maziah, M.; Shaharuddin, N.A.; Sahebi, M.; Yusof, Z.N.B.; Atabaki, N.; Talei, D. A critical review of the concept of transgenic plants: Insights into pharmaceutical biotechnology and molecular farming. Curr. Issues Mol. Biol. 2015, 18, 21–42.
13. Horn, M.; Woodard, S.; Howard, J. Plant molecular farming: Systems and products. Plant Cell Rep. 2004, 22, 711–720.
14. Youm, J.W.; Jeon, J.H.; Kim, H.; Kim, Y.H.; Ko, K.; Joung, H.; Kim, H. Transgenic tomatoes expressing human beta-amyloid for use as a vaccine against alzheimer’s disease. Biotechnol. Lett. 2008, 30, 1839–1845.
15. Chen, Y.; Wang, A.; Zhao, L.; Shen, G.; Cui, L.; Tang, K. Expression of thymosin α1 concatemer in transgenic tomato (solanum lycopersicum) fruits. Biotechnol. Appl. Biochem. 2009, 52, 303–312.
16. Ruhlman, T.; Verma, D.; Samson, N.; Daniell, H. The role of heterologous chloroplast sequence elements in transgene integration and expression. Plant Physiol. 2010, 152, 2088–2104.
17. Oey, M.; Lohse, M.; Kreikemeyer, B.; Bock, R. Exhaustion of the chloroplast protein synthesis capacity by massive expression of a highly stable protein antibiotic. Plant J. 2009, 57, 436–445.
18. Daniell, H.; Datta, R.; Varma, S.; Gray, S.; Lee, S.-B. Containment of herbicide resistance through genetic engineering of the chloroplast genome. Nat. Biotechnol. 1998, 16, 345.
19. Floss, D.M.; Mockey, M.; Zanello, G.; Brosson, D.; Diogon, M.; Frutos, R.; Bruel, T.; Rodrigues, V.; Garzon, E.; Chevaleyre, C. Expression and immunogenicity of the mycobacterial ag85b/esat-6 antigens produced in transgenic plants by elastin-like peptide fusion strategy. BioMed Res. Int. 2010, 2010, 274346.
20. Lakshmi, P.S.; Verma, D.; Yang, X.; Lloyd, B.; Daniell, H. Low cost tuberculosis vaccine antigens in capsules: Expression in chloroplasts, bio-encapsulation, stability and functional evaluation in vitro. PLoS ONE 2013, 8, e54708.
21. Uvarova, E.A.; Belavin, P.A.; Permyakova, N.V.; Zagorskaya, A.A.; Nosareva, O.V.; Kakimzhanova, A.A.; Deineko, E.V. Oral immunogenicity of plant-made mycobacterium tuberculosis esat6 and cfp10. BioMed Res. Int. 2013, 2013, 8.
22. Daniell, H.; Lee, S.-B.; Panchal, T.; Wiebe, P.O. Expression of the native cholera toxin b subunit gene and assembly as functional oligomers in transgenic tobacco chloroplasts. J. Mol. Biol. 2001, 311, 1001–1009.
23. Koya, V.; Moayeri, M.; Leppla, S.H.; Daniell, H. Plant-based vaccine: Mice immunized with chloroplastderived anthrax protective antigen survive anthrax lethal toxin challenge. Infect. Immun. 2005, 73, 8266– 8274.
24. Arlen, P.A.; Singleton, M.; Adamovicz, J.J.; Ding, Y.; Davoodi-Semiromi, A.; Daniell, H. Effective plague vaccination via oral delivery of plant cells expressing f1-v antigens in chloroplasts. Infect. Immun. 2008, 76, 3640–3650.
25. Chan, H.T.; Xiao, Y.; Weldon, W.C.; Oberste, S.M.; Chumakov, K.; Daniell, H. Cold chain and virus-free chloroplast-made booster vaccine to confer immunity against different poliovirus serotypes. Plant Biotechnol. J. 2016, 14, 2190–2200.
26. Zhang, B.; Shanmugaraj, B.; Daniell, H. Expression and functional evaluation of biopharmaceuticals made in plant chloroplasts. Curr. Opin. Chem. Biol. 2017, 38, 17–23.
27. Ahmad, N.; Michoux, F.; Lössl, A.G.; Nixon, P.J. Challenges and perspectives in commercializing plastid transformation technology. J. Exp. Bot. 2016, 67, 5945–5960.
28. Thanavala, Y.; Mahoney, M.; Pal, S.; Scott, A.; Richter, L.; Natarajan, N.; Goodwin, P.; Arntzen, C.J.; Mason, H.S. Immunogenicity in humans of an edible vaccine for hepatitis b. Proc. Natl. Acad. Sci. USA 2005, 102, 3378–3382.
29. Nochi, T.; Takagi, H.; Yuki, Y.; Yang, L.; Masumura, T.; Mejima, M.; Nakanishi, U.; Matsumura, A.; Uozumi, A.; Hiroi, T. Rice-based mucosal vaccine as a global strategy for cold-chain-and needle-free vaccination. Proc. Natl. Acad. Sci. USA 2007, 104, 10986–10991.
30. Tokuhara, D.; Álvarez, B.; Mejima, M.; Hiroiwa, T.; Takahashi, Y.; Kurokawa, S.; Kuroda, M.; Oyama, M.; Kozuka-Hata, H.; Nochi, T. Rice-based oral antibody fragment prophylaxis and therapy against rotavirus infection. J. Clin. Investig. 2013, 123, 3829–3838.
31. Sijmons, P.C.; Dekker, B.M.; Schrammeijer, B.; Verwoerd, T.C.; Van Den Elzen, P.J.; Hoekema, A. Production of correctly processed human serum albumin in transgenic plants. Biotechnology (N Y) 1990, 8, 217.
32. Barta, A.; Sommergruber, K.; Thompson, D.; Hartmuth, K.; Matzke, M.A.; Matzke, A.J. The expression of a nopaline synthase—human growth hormone chimaeric gene in transformed tobacco and sunflower callus tissue. Plant Mol. Biol. 1986, 6, 347–357.
33. McDonald, K.A.; Hong, L.M.; Trombly, D.M.; Xie, Q.; Jackman, A.P. Production of human α-1-antitrypsin from transgenic rice cell culture in a membrane bioreactor. Biotechnol. Prog. 2005, 21, 728–734.
34. Chen, L.; Yang, X.; Luo, D.; Yu, W. Efficient production of a bioactive bevacizumab monoclonal antibody using the 2a self-cleavage peptide in transgenic rice callus. Front. Plant Sci. 2016, 7, 1156.
35. Chen, T.-L.; Lin, Y.-L.; Lee, Y.-L.; Yang, N.-S.; Chan, M.-T. Expression of bioactive human interferongamma in transgenic rice cell suspension cultures. Transgenic Res. 2004, 13, 499–510.
36. Gurusamy, P.D.; Schäfer, H.; Ramamoorthy, S.; Wink, M. Biologically active recombinant human erythropoietin expressed in hairy root cultures and regenerated plantlets of nicotiana tabacum L. PLoS ONE 2017, 12, e0182367.
37. Huang, L.-F.; Liu, Y.-K.; Lu, C.-A.; Hsieh, S.-L.; Yu, S.-M. Production of human serum albumin by sugar starvation induced promoter and rice cell culture. Transgenic Res. 2005, 14, 569–581.
38. Kim, N.-S.; Yu, H.-Y.; Chung, N.-D.; Shin, Y.-J.; Kwon, T.-H.; Yang, M.-S. Production of functional recombinant bovine trypsin in transgenic rice cell suspension cultures. Protein Expr. Purif. 2011, 76, 121– 126.
39. Lee, S.-J.; Park, C.-I.; Park, M.-Y.; Jung, H.-S.; Ryu, W.-S.; Lim, S.-M.; Tan, H.-K.; Kwon, T.-H.; Yang, M.-S.; Kim, D.-I. Production and characterization of human ctla4ig expressed in transgenic rice cell suspension cultures. Protein Expr. Purif. 2007, 51, 293–302.
40. Liu, Y.-K.; Li, Y.-T.; Lu, C.-F.; Huang, L.-F. Enhancement of recombinant human serum albumin in transgenic rice cell culture system by cultivation strategy. New Biotechnol. 2015, 32, 328–334.
41. Shin, Y.J.; Hong, S.Y.; Kwon, T.H.; Jang, Y.S.; Yang, M.S. High level of expression of recombinant human granulocyte-macrophage colony stimulating factor in transgenic rice cell suspension culture. Biotechnol. Bioeng. 2003, 82, 778–783.
42. Kim, T.-G.; Baek, M.-Y.; Lee, E.-K.; Kwon, T.-H.; Yang, M.-S. Expression of human growth hormone in transgenic rice cell suspension culture. Plant Cell Rep. 2008, 27, 885–891.
43. Chung, N.-D.; Kim, N.-S.; Jang, S.-H.; Oh, S.-M.; Jang, S.-H.; Kim, T.-G.; Jang, Y.-S.; Yang, M.-S. Production of functional human vascular endothelial growth factor165 in transgenic rice cell suspension cultures. Enzym. Microb. Technol. 2014, 63, 58–63.
44. Kim, B.-G.; Kim, S.-H.; Kim, N.-S.; Huy, N.-X.; Choi, Y.-S.; Lee, J.-Y.; Jang, Y.-S.; Yang, M.-S.; Kim, T.-G. Production of monoclonal antibody against fima protein from porphyromonas gingivalis in rice cell suspension culture. Plant Cell Tissue Organ Cult. 2014, 118, 293–304.
45. Islam, M.R.; Kim, N.-S.; Jung, J.-W.; Kim, H.-B.; Han, S.-C.; Yang, M.-S. Spontaneous pepsin c-catalyzed activation of human pepsinogen c in transgenic rice cell suspension culture: Production and characterization of human pepsin c. Enzym. Microb. Technol. 2018, 108, 66–73.
46. Conley, A.J.; Joensuu, J.J.; Menassa, R.; Brandle, J.E. Induction of protein body formation in plant leaves by elastin-like polypeptide fusions. BMC Biol. 2009, 7, 48.
47. Kaldis, A.; Ahmad, A.; Reid, A.; McGarvey, B.; Brandle, J.; Ma, S.; Jevnikar, A.; Kohalmi, S.E.; Menassa, R. High-level production of human interleukin-10 fusions in tobacco cell suspension cultures. Plant Biotechnol. J. 2013, 11, 535–545.
48. Joseph, M.; Ludevid, M.D.; Torrent, M.; Rofidal, V.; Tauzin, M.; Rossignol, M.; Peltier, J.-B. Proteomic characterisation of endoplasmic reticulum-derived protein bodies in tobacco leaves. BMC Plant Biol. 2012, 12, 36.
49. Torrent, M.; Llop-Tous, I.; Ludevid, M.D. Protein body induction: A new tool to produce and recover recombinant proteins in plants. In Recombinant Proteins from Plants; Springer: Berlin, Germany, 2009; pp. 193–208.
50. Reuter, L.J.; Bailey, M.J.; Joensuu, J.J.; Ritala, A. Scale-up of hydrophobin-assisted recombinant protein production in tobacco by-2 suspension cells. Plant Biotechnol. J. 2014, 12, 402–410.
51. Joensuu, J.J.; Conley, A.J.; Lienemann, M.; Brandle, J.E.; Linder, M.B.; Menassa, R. Hydrophobin fusions for high-level transient protein expression and purification in nicotiana benthamiana. Plant Physiol. 2010, 152, 622–633.
52. Gutiérrez, S.P.; Saberianfar, R.; Kohalmi, S.E.; Menassa, R. Protein body formation in stable transgenic tobacco expressing elastin-like polypeptide and hydrophobin fusion proteins. BMC Biotechnol. 2013, 13, 40.
53. Huang, Z.; Phoolcharoen, W.; Lai, H.; Piensook, K.; Cardineau, G.; Zeitlin, L.; Whaley, K.J.; Arntzen, C.J.; Mason, H.S.; Chen, Q. High-level rapid production of full-size monoclonal antibodies in plants by a singlevector DNA replicon system. Biotechnol. Bioeng. 2010, 106, 9–17.
54. Moon, K.-B.; Lee, J.; Kang, S.; Kim, M.; Mason, H.S.; Jeon, J.-H.; Kim, H.-S. Overexpression and selfassembly of virus-like particles in nicotiana benthamiana by a single-vector DNA replicon system. Appl. Microbiol. Biotechnol. 2014, 98, 8281–8290.
55. Fujiuchi, N.; Matsuda, R.; Matoba, N.; Fujiwara, K. Effect of nitrate concentration in nutrient solution on hemagglutinin content of nicotiana benthamiana leaves in a viral vector-mediated transient gene expression system. Plant Biotechnol. 2014, 31, 207–211.
56. Fujiuchi, N.; Matsuda, R.; Matoba, N.; Fujiwara, K. Removal of bacterial suspension water occupying the intercellular space of detached leaves after agroinfiltration improves the yield of recombinant hemagglutinin in a nicotiana benthamiana transient gene expression system. Biotechnol. Bioeng. 2016, 113, 901–906.
57. Fujiuchi, N.; Matsuda, R.; Matoba, N.; Fujiwara, K. Effects of plant density on recombinant hemagglutinin yields in an agrobacterium-mediated transient gene expression system using nicotiana benthamiana plants. Biotechnol. Bioeng. 2017, 114, 1762–1770.
58. Moon, K.-B.; Jeon, J.-H.; Lee, W.-S.; Kim, H. Transient erythropoietin overexpression with cucumber mosaic virus suppressor 2b in nicotiana benthamiana. Hortic. Environ. Biotechnol. 2012, 53, 434–440.
59. Merlin, M.; Gecchele, E.; Arcalis, E.; Remelli, S.; Brozzetti, A.; Pezzotti, M.; Avesani, L. Enhanced gad65 production in plants using the magnicon transient expression system: Optimization of upstream production and downstream processing. Biotechnol. J. 2016, 11, 542–553.
60. Testa, D.; Liao, M.-J.; Ferencz-Biro, K.; Rashidbaigi, A.; DiPaola, M. Composition Containing Human Alpha Interferon Species Proteins and Method for Use Thereof. U.S. Patent 5,676,942, 14 October 1997.
61. Huang, T.-K.; McDonald, K.A. Bioreactor engineering for recombinant protein production in plant cell suspension cultures. Biochem. Eng. J. 2009, 45, 168–184.
62. Xu, J.; Ge, X.; Dolan, M.C. Towards high-yield production of pharmaceutical proteins with plant cell suspension cultures. Biotechnol. Adv. 2011, 29, 278–299.
63. Vermij, P.; Waltz, E. Usda approves the first plant-based vaccine. Nat. Biotechnol. 2006, 24, 234.
64. Mor, T.S. Molecular pharming’s foot in the fda’s door: Protalix’s trailblazing story. Biotechnol. Lett. 2015, 37, 2147–2150.
65. Rosales-Mendoza, S.; Tello-Olea, M.A. Carrot cells: A pioneering platform for biopharmaceuticals production. Mol. Biotechnol. 2015, 57, 219–232.
66. Lu, C.-A.; Lim, E.-K.; Yu, S.-M. Sugar response sequence in the promoter of a rice α-amylase gene serves as a transcriptional enhancer. J. Biol. Chem. 1998, 273, 10120–10131.
67. Fischer, R.; Schillberg, S.; Hellwig, S.; Twyman, R.M.; Drossard, J. Gmp issues for recombinant plantderived pharmaceutical proteins. Biotechnol. Adv. 2012, 30, 434–439.
68. Sparrow, P.; Broer, I.; E Hood, E.; Eversole, K.; Hartung, F.; Schiemann, J. Risk assessment and regulation of molecular farming-a comparison between europe and us. Curr. Pharm. Des. 2013, 19, 5513–5530.
69. Pogue, G.P.; Vojdani, F.; Palmer, K.E.; Hiatt, E.; Hume, S.; Phelps, J.; Long, L.; Bohorova, N.; Kim, D.; Pauly, M. Production of pharmaceutical-grade recombinant aprotinin and a monoclonal antibody product using plant-based transient expression systems. Plant Biotechnol. J. 2010, 8, 638–654.
70. Fujiuchi, N.; Matoba, N.; Matsuda, R. Environment control to improve recombinant protein yields in plants based on agrobacterium-mediated transient gene expression. Front. Bioeng. Biotechnol. 2016, 4, 23.
71. Twyman, R.M.; Schillberg, S.; Fischer, R. Optimizing the yield of recombinant pharmaceutical proteins in plants. Curr. Pharm. Des. 2013, 19, 5486–5494.
72. Stoger, E.; Sack, M.; Perrin, Y.; Vaquero, C.; Torres, E.; Twyman, R.M.; Christou, P.; Fischer, R. Practical considerations for pharmaceutical antibody production in different crop systems. Mol. Breed. 2002, 9, 149– 158.
73. Sala, F.; Rigano, M.M.; Barbante, A.; Basso, B.; Walmsley, A.M.; Castiglione, S. Vaccine antigen production in transgenic plants: Strategies, gene constructs and perspectives. Vaccine 2003, 21, 803–808.
74. Twyman, R.M.; Stoger, E.; Schillberg, S.; Christou, P.; Fischer, R. Molecular farming in plants: Host systems and expression technology. TRENDS Biotechnol. 2003, 21, 570–578.
75. Devos, Y.; Reheul, D.; Schrijver, A.D.; Cors, F.; Moens, W. Management of herbicide-tolerant oilseed rape in europe: A case study on minimizing vertical gene flow. Environ. Biosaf. Res. 2004, 3, 135–148.
76. Hood, E.E.; Witcher, D.R.; Maddock, S.; Meyer, T.; Baszczynski, C.; Bailey, M.; Flynn, P.; Register, J.; Marshall, L.; Bond, D. Commercial production of avidin from transgenic maize: Characterization of transformant, production, processing, extraction and purification. Mol. Breed. 1997, 3, 291–306.
77. Federation of American scientists (FAS): The Prodigene Incident. Available online: https://fas.org/biosecurity/education/dualuse-agriculture/2.-agricultural-biotechnology/prodigene-incident.html (accessed on 24. Dec.2019)
78. Boothe, J.; Nykiforuk, C.; Kuhlman, P.; Whelan, H.; Pollock, W.; Clark, S.; Yuan, S.; Kumar, R.; Murray, E.; Visser, F. Analytical characterization, safety and clinical bioequivalence of recombinant human insulin from transgenic plants. In 69th Scientific Sessions; Abstract; American Diabetes Association: Arlington County, VA, USA, 2009; Volume 5.
79. Breyer, D.; Goossens, M.; Herman, P.; Sneyers, M. Biosafety considerations associated with molecular farming in genetically modified plants. J. Med. Plants Res. 2009, 3, 825–838.
80. McPherson, M.A.; Yang, R.-C.; Good, A.G.; Nielson, R.L.; Hall, L.M. Potential for seed-mediated gene flow in agroecosystems from transgenic safflower (Carthamus tinctorius L.) intended for plant molecular farming. Transgenic Res. 2009, 18, 281–299.
81. Ruf, S.; Karcher, D.; Bock, R. Determining the transgene containment level provided by chloroplast transformation. Proc. Natl. Acad. Sci. USA 2007, 104, 6998–7002.
82. Svab, Z.; Maliga, P. Exceptional transmission of plastids and mitochondria from the transplastomic pollen parent and its impact on transgene containment. Proc. Natl. Acad. Sci. USA 2007, 104, 7003–7008.
83. Arlen, P.A.; Falconer, R.; Cherukumilli, S.; Cole, A.; Cole, A.M.; Oishi, K.K.; Daniell, H. Field production and functional evaluation of chloroplast-derived interferon-α2b. Plant Biotechnol. J. 2007, 5, 511–525.
84. Zavaleta, N.; Figueroa, D.; Rivera, J.; Sánchez, J.; Alfaro, S.; Lönnerdal, B. Efficacy of rice-based oral rehydration solution containing recombinant human lactoferrin and lysozyme in peruvian children with acute diarrhea. J. Pediatr. Gastroenterol. Nutr. 2007, 44, 258–264.
85. MacManus, C.F.; Collins, C.B.; Nguyen, T.T.; Alfano, R.W.; Jedlicka, P.; de Zoeten, E.F. Ven-120, a recombinant human lactoferrin, promotes a regulatory t cell [treg] phenotype and drives resolution of inflammation in distinct murine models of inflammatory bowel disease. J. Crohn’s Colitis 2017, 11, 1101– 1112.
86. Kozai, T.; Afreen, F.; Zobayed, S.M. Photoautotrophic (Sugar-Free Medium) Micropropagation as a New Micropropagation and Transplant Production System; Springer Science & Business Media: Berlin, Germany, 2005.
87. Farran, I.; Río-Manterola, F.; Íñiguez, M.; Gárate, S.; Prieto, J.; Mingo-Castel, A.M. High-density seedling expression system for the production of bioactive human cardiotrophin-1, a potential therapeutic cytokine, in transgenic tobacco chloroplasts. Plant Biotechnol. J. 2008, 6, 516–527.
88. Ho, L. The contribution of plant physiology in glasshouse tomato soilless culture. In South Pacific Soilless Culture Conference-SPSCC 648; ISHS: Leuven, Belgium, 2003; pp. 19–25.
89. Jones, J.B., Jr. Tomato Plant Culture: In the Field, Greenhouse, and Home Garden; CRC Press: Boca Raton, FL, USA, 2007.
90. Kubota, C.; Thomson, C.A.; Wu, M.; Javanmardi, J. Controlled environments for production of value-added food crops with high phytochemical concentrations: Lycopene in tomato as an example. HortScience 2006, 41, 522–525.
91. Pniewski, T.; Czyż, M.; Wyrwa, K.; Bociąg, P.; Krajewski, P.; Kapusta, J. Micropropagation of transgenic lettuce containing hbsag as a method of mass-scale production of standardised plant material for biofarming purposes. Plant Cell Rep. 2017, 36, 49–60.
92. Pujol, M.; Ramírez, N.I.; Ayala, M.; Gavilondo, J.V.; Valdés, R.; Rodríguez, M.; Brito, J.; Padilla, S.; Gómez, L.; Reyes, B. An integral approach towards a practical application for a plant-made monoclonal antibody in vaccine purification. Vaccine 2005, 23, 1833–1837.
93. Paul, M.; Reljic, R.; Klein, K.; Drake, P.M.; van Dolleweerd, C.; Pabst, M.; Windwarder, M.; Arcalis, E.; Stoger, E.; Altmann, F. Characterization of a plant-produced recombinant human secretory IgA with broad neutralizing activity against HIV. mAbs 2014, 6, 1585–1597.
94. Magnusdottir, A.; Vidarsson, H.; Björnsson, J.M.; Örvar, B.L. Barley grains for the production of endotoxinfree growth factors. Trends Biotechnol. 2013, 31, 572–580.
95. Haberlandt, G. Experiments on the culture of isolated plant cells. Bot. Rev. 1969, 35, 68–88.
96. Wilson, S.A.; Roberts, S.C. Recent advances towards development and commercialization of plant cell culture processes for the synthesis of biomolecules. Plant Biotechnol. J. 2012, 10, 249–268.
97. Santos, R.B.; Abranches, R.; Fischer, R.; Sack, M.; Holland, T. Putting the spotlight back on plant suspension cultures. Front. Plant Sci. 2016, 7, 297.
98. Holland, T.; Buyel, J.F. Bioreactor-based production of glycoproteins in plant cell suspension cultures. In Recombinant Glycoprotein Production; Springer: Berlin, Germany, 2018; pp. 129–146.
99. Trexler, M.M.; McDonald, K.A.; Jackman, A.P. A cyclical semicontinuous process for production of human α1-antitrypsin using metabolically induced plant cell suspension cultures. Biotechnol. Prog. 2005, 21, 321– 328.
100. Barretto, S.; Michoux, F.; Nixon, P.J. Temporary immersion bioreactors for the contained production of recombinant proteins in transplastomic plants. In Recombinant Proteins from Plants; Springer: Berlin, Germany, 2016; pp. 149–160.
101. Michoux, F.; Ahmad, N.; McCarthy, J.; Nixon, P.J. Contained and high-level production of recombinant protein in plant chloroplasts using a temporary immersion bioreactor. Plant Biotechnol. J. 2011, 9, 575–584.
102. Michoux, F.; Ahmad, N.; Hennig, A.; Nixon, P.J.; Warzecha, H. Production of leafy biomass using temporary immersion bioreactors: An alternative platform to express proteins in transplastomic plants with drastic phenotypes. Planta 2013, 237, 903–908.
103. Kang, T.-J.; Lee, W.-S.; Choi, E.-G.; Kim, J.-W.; Kim, B.-G.; Yang, M.-S. Mass production of somatic embryos expressing escherichia coli heat-labile enterotoxin b subunit in siberian ginseng. J. Biotechnol. 2006, 121, 124– 133.
104. Týcová, A.; Piernikarczyk, R.J.; Kugler, M.; Lipovová, P.; Podzimek, T.; Steger, G.; Matoušek, J. A 5′ p degradation hot spot influences molecular farming of anticancerogenic nuclease tbn1 in tobacco cells. Plant Cell Tissue Organ Cult. 2016, 127, 347–358.
105. Buyel, J.F.; Twyman, R.M.; Fischer, R. Very-large-scale production of antibodies in plants: The biologization of manufacturing. Biotechnol. Adv. 2017, 35, 458–465.
106. Eibl, R.; Kaiser, S.; Lombriser, R.; Eibl, D. Disposable bioreactors: The current state-of-the-art and recommended applications in biotechnology. Appl. Microbiol. Biotechnol. 2010, 86, 41–49.
107. Eibl, R.; Eibl, D. Design of bioreactors suitable for plant cell and tissue cultures. Phytochem. Rev. 2008, 7, 593–598.
108. Georgiev, M.I.; Eibl, R.; Zhong, J.-J. Hosting the plant cells in vitro: Recent trends in bioreactors. Appl. Microbiol. Biotechnol. 2013, 97, 3787–3800.
109. Raven, N.; Schillberg, S.; Rasche, S. Plant cell-based recombinant antibody manufacturing with a 200 L orbitally shaken disposable bioreactor. In Recombinant Proteins from Plants; Springer: Berlin, Germany, 2016; pp. 161–172.
110. Raven, N.; Rasche, S.; Kuehn, C.; Anderlei, T.; Klöckner, W.; Schuster, F.; Henquet, M.; Bosch, D.; Büchs, J.; Fischer, R. Scaled-up manufacturing of recombinant antibodies produced by plant cells in a 200-l orbitallyshaken disposable bioreactor. Biotechnol. Bioeng. 2015, 112, 308–321.
111. Corbin, J.M.; Hashimoto, B.I.; Karuppanan, K.; Kyser, Z.R.; Wu, L.; Roberts, B.A.; Noe, A.R.; Rodriguez, R.L.; McDonald, K.A.; Nandi, S. Semicontinuous bioreactor production of recombinant butyrylcholinesterase in transgenic rice cell suspension cultures. Front. Plant Sci. 2016, 7, 412.
112. Holtz, B.R.; Berquist, B.R.; Bennett, L.D.; Kommineni, V.J.; Munigunti, R.K.; White, E.L.; Wilkerson, D.C.; Wong, K.Y.I.; Ly, L.H.; Marcel, S. Commercial-scale biotherapeutics manufacturing facility for plant-made pharmaceuticals. Plant Biotechnol. J. 2015, 13, 1180–1190.
113. Matsuda, R.; Kubota, C.; Alvarez, M.L.; Cardineau, G.A. Biopharmaceutical protein production under controlled environments: Growth, development, and vaccine productivity of transgenic tomato plants grown hydroponically in a greenhouse. HortScience 2009, 44, 1594–1599.
114. Matsuda, R.; Kubota, C.; Alvarez, M.L.; Cardineau, G.A. Effect of high electrical conductivity of hydroponic nutrient solution on vaccine protein content in transgenic tomato. HortTechnology 2012, 22, 362–367.
115. Matsuda, R.; Kubota, C.; Alvarez, M.L.; Cardineau, G.A. Determining the optimal timing of fruit harvest in transgenic tomato expressing f1-v, a candidate subunit vaccine against plague. HortScience 2010, 45, 347– 351.
116. Su, J.; Zhu, L.; Sherman, A.; Wang, X.; Lin, S.; Kamesh, A.; Norikane, J.H.; Streatfield, S.J.; Herzog, R.W.; Daniell, H. Low cost industrial production of coagulation factor ix bioencapsulated in lettuce cells for oral tolerance induction in hemophilia b. Biomaterials 2015, 70, 84–93.
117. Kashima, K.; Yuki, Y.; Mejima, M.; Kurokawa, S.; Suzuki, Y.; Minakawa, S.; Takeyama, N.; Fukuyama, Y.; Azegami, T.; Tanimoto, T. Good manufacturing practices production of a purification-free oral cholera vaccine expressed in transgenic rice plants. Plant Cell Rep. 2016, 35, 667–679.
118. Tabayashi, N.; Matsumura, T. Forefront study of plant biotechnology for practical use: Development of oral drug for animal derived from transgenic strawberry. Soc. Biotechnol. J. Japn 2014, 92, 537–539.
119. McCormick, A.; Reddy, S.; Reinl, S.; Cameron, T.; Czerwinkski, D.; Vojdani, F.; Hanley, K.; Garger, S.; White, E.; Novak, J. Plant-produced idiotype vaccines for the treatment of non-hodgkin’s lymphoma: Safety and immunogenicity in a phase i clinical study. Proc. Natl. Acad. Sci. USA 2008, 105, 10131–10136.