Plants as factories for human pharmaceuticals: Applications and challenges

International Journal of Molecular Sciences

Volumn 16, Issue 12, 2015, Pages 28549-28565

  Yao, Jian ^a   Weng, Yunqi ^a   Dickey, Alexia ^b   Wang, Kevin Yueju ^b  

^a QINGDAO UNIVERSITY   (China)

^b NORTHEASTERN STATE UNIVERSITY   (United States)

Author keywords

Edible vaccine; Humanized glycan; Plant molecular farming; Seed platform; Transient expression

Indexed keywords

EDIBLE VACCINE; GLYCAN; GLYCOPROTEIN; MONOCLONAL ANTIBODY; RECOMBINANT PROTEIN; VASCULOTROPIN; VEGETABLE PROTEIN; VIRUS VECTOR; PLANT MEDICINAL PRODUCT; POLYSACCHARIDE;

BACTERIAL COLONIZATION; BIOSAFETY; CLINICAL TRIAL (TOPIC); COMMERCIAL PHENOMENA; DIET SUPPLEMENTATION; DRUG INDUSTRY; DRUG RESEARCH; EBOLA HEMORRHAGIC FEVER; ESCHERICHIA COLI; GLYCOSYLATION; GOOD MANUFACTURING PRACTICE; HUMAN; IMMUNOGENICITY; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; NONHUMAN; PLANT BIOTECHNOLOGY; PLANT CELL CULTURE; PLANT GENOME; PLANT MOLECULAR FARMING; PROTEIN DEGRADATION; PROTEIN STABILITY; REVIEW; SOYBEAN; TRANSGENE; TRANSIENT EXPRESSION; VIRIDIPLANTAE; YEAST; BATCH CELL CULTURE; BIOREACTOR; BIOTECHNOLOGY; CHEMISTRY; GENETIC ENGINEERING; GENETICS; ISOLATION AND PURIFICATION; MEDICINAL PLANT; METABOLISM; PLANT CELL; PROCEDURES; TRADITIONAL MEDICINE; TRANSGENIC PLANT;

BATCH CELL CULTURE TECHNIQUES; BIOREACTORS; BIOTECHNOLOGY; GENETIC ENGINEERING; GLYCOSYLATION; HUMANS; MEDICINE, TRADITIONAL; PLANT CELLS; PLANT PREPARATIONS; PLANTS, GENETICALLY MODIFIED; PLANTS, MEDICINAL; POLYSACCHARIDES;

EID: 84949472031     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms161226122     Document Type: Review

References (110)

1. Arntzen, C. Plant-made pharmaceuticals: From “Edible Vaccines” to Ebola therapeutics. Plant Biotechnol. 2015, 13, 1013-1016. [CrossRef] [PubMed]
2. Mapp Biopharmaceutical, Inc. Home Page. Available online: http://mappbio.com (accessed on 27 November 2015).
3. World Health organization Middle East respiratory syndrome coronavirus (MERS-CoV) Updates Home Page. Available online: http://www.who.int/emergencies/mers-cov/en/ (accessed on 27 November 2015).
4. Planet Biotechnology Inc. Home Page. Available online: http://www.planetbiotechnology.com (accessed on 27 November 2015).
5. Barta, A.; Sommengruber, K.; Thompson, D.; Hartmuth, K.; Matzke, M.; Matzke, A. The expression of a napoline synthase human growth hormone chimeric gene in transformed tobacco and sunflower callus tissue. Plant Mol. Biol. 1986, 6, 347-357. [CrossRef] [PubMed]
6. Mason, H.S.; Lam, D.M.; Arntzen, C.J. Expression of hepatitis B surface antigen in transgenic plants. Proc. Natl. Acad. Sci. USA 1992, 89, 11745-11749. [CrossRef] [PubMed]
7. Paul, M.; Ma, J.K. Plant-made pharmaceuticals: Leading products and production platforms. Biotechnol. Appl. Biochem. 2011, 58, 58-67. [CrossRef] [PubMed]
8. Boothe, J.; Nykiforuk, C.; Shen, Y.; Zaplachinski, S.; Szarka, S.; Kuhlman, P.; Murray, E.; Morck, D.; Moloney, M.M. Seed-based expression systems for plant molecular farming. Plant Biotechnol. J. 2010, 8, 588-606. [CrossRef] [PubMed]
9. Sack, M.; Rademacher, T.; Spiegel, H.; Boes, A.; Hellwig, S.; Drossard, J.; Stoger, E.; Fischer, R. From gene to harvest: Insights into upstream process development for the GMP production of a monoclonal antibody in transgenic tobacco plants. Plant Biotechnol. J. 2015. [CrossRef] [PubMed]
10. Abiri, R.; Valdiani, A.; Maziah, M.; Shaharuddin, N.A.; Sahebi, M.; Yusof, Z.Y.; 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. [PubMed]
11. Gomord, V.; Fitchette, A.C.; Menu-Bouaouiche, L.; Saint-Jore-Dupas, C.; Plasson, C.; Michaud, D.; Faye, L. Plant-specific glycosylation patterns in the context of therapeutic protein production. Plant Biotechnol. J. 2010, 8, 564-587. [CrossRef] [PubMed]
12. Ullrich, K.K.; Hiss, M.; Rensing, S.A. Means to optimize protein expression in transgenic plants. Curr. Opin. Biotechnol. 2015, 32, 61-67. [CrossRef] [PubMed]
13. Kristina, K. L.; Zeng, W.; Heazlewood, J.L.; Bacic, A. Characterization of protein N-glycosylation by tandem mass spectrometry using complementary fragmentation techniques. Front. Plant Sci. 2015, 6. [CrossRef]
14. Buyel, J.F.; Fischer, R. A juice extractor can simplify the downstream processing of plant-derived biopharmaceutical proteins compared to blade-based homogenizers. Process Biochem. 2014, 50, 859-866. [CrossRef]
15. Buyel, J.F.; Twyman, R.M.; Fischer, R. Extraction and downstream processing of plant-derived recombinant proteins. Biotechnol. Adv. 2015, 33, 902-913. [CrossRef] [PubMed]
16. Fischer, R.; Vasilev, N.; Twyman, R.M.; Schillberg, S. High-value products from plants: The challenges of process optimization. Curr. Opin. Biotechnol. 2015, 32, 56-62. [CrossRef] [PubMed]
17. Fox, J.L. First plant-made biologic approved. Nat. Biotechnol. 2012, 30. [CrossRef]
18. U.S. National Institutes of Health Clinical Trial Home Page. Available online: https://clinicaltrials.gov (accessed on 27 November 2015).
19. Protealix Biotherapeutics Home Page. Available online: https://www.protalix.com (accessed on 27 November 2015).
20. Icon Genetics GmbH Home Page. Available online: https://www.icongenetics.com (accessed on 27 November 2015).
21. Ventria Biosciences Home Page. Available online: https://www.ventria.com (accessed on 27 November 2015).
22. Greenovation Biotech GmbH Home Page. Available online: https://www.greenovation.com (accessed on 27 November 2015).
23. Kentucky BioProcessing Home Page. Available online: https://www.kbpllc.com (accessed on 27 November 2015).
24. PhycoBiologics Inc., Home Page. Available online: https://www.phycotransgenics.com (accessed on 27 November 2015).
25. Medicago Home Page. Available online: https://www.medicago.com (accessed on 27 November 2015).
26. Synthon Home Page. Available online: http://www.synthon.com (accessed on 27 November 2015).
27. Fraunhofer IME Home Page. Available online: http://www.ime.fraunhofer.de (accessed on 27 November 2015).
28. Fraunhofer CMB Home Page. Available online: http://www.fhcmb.org (accessed on 27 November 2015).
29. Healthgen Biotechnology Home Page. Available online: http://www.oryzogen.com (accessed on 27 November 2015).
30. Walmsley, A.M.; Arntsen, C.J. Plants for delivery of edible vaccines. Curr. Opin. Biotechnol. 2000, 22, 126-129. [CrossRef]
31. Fukuda, K.; Ishida, W.; Harada, Y.; Wakasa, Y.; Takagi, H.; Takaiwa, F.; Fukushima, A. Prevention of allergic conjunctivitis in mice by a rice-based edible vaccine containing modified Japanese cedar pollen allergens. Br. J. Ophthalmol. 2015, 99, 705-709. [CrossRef] [PubMed]
32. Barzegari, A.; Saeedi, N.; Zarredar, H.; Barar, J.; Omidi, Y. The search for a promising cell factory system for production of edible vaccine. Hum. Vaccines Immunother. 2014, 10, 2497-2502. [CrossRef] [PubMed]
33. Lee, G.; Na, Y.J.; Yang, B.G.; Choi, J.P.; Seo, Y.B.; Hong, C.P.; Yun, C.H.; Kim, D.H.; Sohn, E.J.; Kim, J.H. et al. Oral immunization of haemaggulutinin H5 expressed in plant endoplasmic reticulum with adjuvant saponin protects mice against highly pathogenic avian influenza A virus infection. Plant Biotechnol. J. 2015, 13, 62-72. [CrossRef] [PubMed]
34. Rosales-Mendoza, S.; Salazar-González, J.A. Immunological aspects of using plant cells as delivery vehicles for oral vaccines. Expert Rev. Vaccines 2014, 13, 737-749. [CrossRef] [PubMed]
35. Aboul-Ata, A.A.; Vitti, A.; Nuzzaci, M.; El-Attar, A.K.; Piazzolla, G.; Tortorella, C.; Harandi, A.M.; Olson, O.; Wright, S.A.; Piazzolla, P. Plant-based vaccines: Novel and low-cost possible route for Mediterranean innovative vaccination strategies. Adv. Virus Res. 2014, 89, 1-37. [PubMed]
36. Kong, Q.; Richter, L.; Yang, Y.F.; Arntzen, C.J.; Mason, H.S.; Thanavala, Y. Oral immunization with hepatitis B surface antigen expressed in transgenic plants. Proc. Natl. Acad. Sci. USA 2001, 98, 11539-11544. [CrossRef] [PubMed]
37. 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. [CrossRef] [PubMed]
38. Hefferon, K. Clinical trials fuel the promise of plant-derived vaccines. Am. J. Clin. Med. 2010, 7, 30-37.
39. Antibodies-online Inc. Home Page. Available online: http://www.antibodies-online.com (accessed on 27 November 2015).
40. PromoKine Home Page. Available online: https://www.promokine.info (accessed on 27 November 2015).
41. Spök, A.; Karner, S. Plant Molecular Farming, Opportunities and Challenges; JRC Technical Report EUR 23383 EN; Office for Official Publications of the European Communities: Kopstal, Luxembourg, 2008.
42. Sabalza, M.; Christou, P.; Capell, T. Recombinant plant-derived pharmaceutical proteins: Current technical and economic bottlenecks. Biotechnol. Lett. 2014, 36, 2367-2379. [CrossRef] [PubMed]
43. Lallemand, J.; Bouché, F.; Desiron, C.; Stautemas, J.; de LemosEsteves, F.; Périlleux, C.; Tocquin, P. Extracellular peptidase hunting for improvement of protein production in plant cells and roots. Front. Plant Sci. 2015, 6. [CrossRef] [PubMed]
44. Breyer, D.; Goossens, M.; Herman, P.; Sneyers, M. Biosafety considerations associated with molecular farming in genetically modified plants. J. Med. Plant Res. 2009, 3, 825-838.
45. Sparrow, P.; Broer, I.; Hood, E.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. [CrossRef] [PubMed]
46. MacDonald, J.; Doshi, K.; Dussault, M.; Hall, J.C.; Holbrook, L.; Jones, G.; Kaldis, A.; Klima, C.L.; Macdonald, P.; McAllister, T.; et al. Bringing plant-based veterinary vaccines to market: Managing regulatory and commercial hurdles. Biotechnol. Adv. 2015. [CrossRef] [PubMed]
47. FDA guidance for industry: Drugs, biologics, and medical devices derived from bioengineered plants for use in humans and animals (draft guidance). FDA website. Available online: Http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm055424.pdf (accessed on 27 November 2015).
48. Strauss, D.M. Liability for genetically modified food: Are GMOs a tort waiting to happen? SciTech Lawyer 2012, 9, 8-13.
49. Jin, C.; Altmann, F.; Strasser, R.; Mach, L.; Schähs, M.; Kunert, R.; Rademacher, T.; Glössl, J.; Steinkellner, H. A plant-derived human monoclonal antibody induces an anti-carbohydrate immune response in rabbits. Glycobiology 2008, 18, 235-241. [CrossRef] [PubMed]
50. Mari, A. IgE to cross-reactive carbohydrate determinants: Analysis of the distribution and appraisal of the in vivo and in vitro reactivity. Int. Arch. Allergy Immunol. 2002, 129, 286-295. [CrossRef] [PubMed]
51. Costa, A.R.; Rodrigues, M.E.; Henriques, M.; Oliveira, R.; Azeredo, J. Glycosylation: Impact, control and improvement during therapeutic protein production. Crit. Rev. Biotechnol. 2014, 34, 281-299. [CrossRef] [PubMed]
52. Bardor, M.; Faveeuw, C.; Fitchette, A.C.; Gilbert, D.; Galas, L.; Trottein, F.; Faye, L.; Lerouge, P. Immunoreactivity in mammals of two typical plant glyco-epitopes, core alpha(1,3)-fucose and core xylose. Glycobiology 2003, 13, 427-434. [CrossRef] [PubMed]
53. Castilho, A.; Steinkellner, H. Glyco-engineering in plants to produce human-like N-glycan structures. Biotechnol. J. 2012, 7, 1088-1098. [CrossRef] [PubMed]
54. Ma, J.K.C.; Hikmat, B.Y.; Wycoff, K.; Vine, N.D.; Chargelegue, D.; Yu, L.; Hein, M.B.; Lherner, T. Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat. Med. 1998, 4, 601-606. [CrossRef] [PubMed]
55. Zeitlin, L.; Olmsted, S.S.; Moench, T.C.; Co, M.S.; Martinell, B.J.; Paradkar, V.M.; Russell, D.R.; Queen, C.; Cone, R.A.; Whaley, K. A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes. Nat. Biotechnol. 1998, 16, 1361-1364. [PubMed]
56. Tan, Y.; Wang, K.Y.; Wang, N.; Li, G.; Liu, D. Ectopic expression of human acidic fibroblast growth factor 1 in the medicinal plant, Salvia miltiorrhiza, accelerates the healing of burn wounds. BMC Biotechnol. 2014, 14. [CrossRef] [PubMed]
57. Guan, C.; Ji, J.; Jin, C.; Wang, G.; Li, X.; Guan, W. Expression of cholera toxin B subunit-lumbrokinase in edible sunflower seeds-the use of transmucosal carrier to enhance its fusion protein’s effect on protection of rats and mice against thrombosis. Biotechnol. Prog. 2014, 30, 1029-1039. [CrossRef] [PubMed]
58. Guan, C.; Du, X.; Wang, G.; Ji, J.; Jin, C.; Li, X. Expression of biologically active anti-thrombosis protein lumbrokinase in edible sunflower seed kernel. J. Plant Biochem. Biotechnol. 2014, 23, 257-265. [CrossRef]
59. Wang, K.; Tull, L.; Cooper, E.; Wang, N.; Liu, D. Recombinant protein production of earthworm lumbrokinase for potential antithrombotic application. Evid. Based Complement. Altern. Med. 2013, 783971. [CrossRef] [PubMed]
60. Andrews, L.B.; Curtis, W.R. Comparison of transient protein expression in tobacco leaves and plant suspension culture. Biotechnol. Prog. 2005, 21, 946-952. [CrossRef] [PubMed]
61. Sainsbury, F.; Lomonossoff, G.P. Transient expressions of synthetic biology in plants. Curr. Opin. Plant Biol. 2014, 19, 1-7. [CrossRef] [PubMed]
62. Peyret, H.; Lomonossoff, G.P. When plant virology met Agrobacterium: The rise of the deconstructed clones. Plant Biotechnol. J. 2015, 13, 1121-1135. [CrossRef] [PubMed]
63. Catrice, E.V.; Sainsbury, F. Assembly and purification of polyomavirus-like particles from plants. Mol. Biotechnol. 2015, 57, 904-913. [CrossRef] [PubMed]
64. 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 single-vector DNA replicon system. Biotechnol. Bioeng. 2010, 106, 9-17. [CrossRef] [PubMed]
65. Qiu, X. Wong, G. Audet, J. Bello, A.; Fernando, L. Alimonti, J. B. Fausther-Bovendo, H. Wei, H. Aviles, J. Hiatt, E. et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 2014, 514, 47-53. [CrossRef] [PubMed]
66. U.S. Department of Health & Human Service: Partnership advances experimental Ebola drug. Available online: http://www.hhs.gov/about/news/2015/07/20/hhs-partnership-advances-experimental-eboladrug. html (accessed on 27 November 2015).
67. Schillberg, S.; Raven, N.; Fischer, R.; Twyman, R.M.; Schiermeyer, A. Molecular farming of pharmaceutical proteins using plant suspension cell and tissue cultures. Curr. Pharm. 2013, 19, 5531-5542. [CrossRef]
68. Magy, B.; Tollet, J.; Laterre, R.; Boutry, M.; Navarre, C. Accumulation of secreted antibodies in plant cell cultures varies according to the isotype, host species and culture conditions. Plant Biotechnol. J. 2014, 12, 457-467. [CrossRef] [PubMed]
69. Raven, N.; Rasche, S.; Kuehn, C.; Anderlei, T.; Klöckner, W.; Schuster, F.; Henquet, M.; Bosch, D.; Büchs, J.; Fischer, R. et al. Scaled-up manufacturing of recombinant antibodies produced by plant cells in a 200-L orbitally-shaken disposable bioreactor. Biotechnol. Bioeng. 2015, 112, 308-321. [CrossRef] [PubMed]
70. Tekoah, Y.; Shulman, A.; Kizhner, T.; Ruderfer, I.; Fux, L.; Nataf, Y.; Bartfeld, D.; Ariel, T.; Gingis-Velitski, S.; Hanania, U. et al. Large-scale production of pharmaceutical proteins in plant cell culture-the protalix experience. Plant Biotechnol. J. 2015, 13, 1199-1208. [CrossRef] [PubMed]
71. Huang, T.K.; McDonald, K.A. Bioreactor systems for in vitro production of foreign proteins using plant cell cultures. Biotechnol. Adv. 2012, 30, 398-409. [CrossRef] [PubMed]
72. Kircheis, R.; Halanek, N.; Koller, I.; Jost, W.; Schuster, M.; Gorr, G.; Hajszan, K.; Nechansky, A. Correlation of ADCC activity with cytokine release induced by the stably expressed, glyco-engineered humanized Lewis Y-specific monoclonal antibody MB 314. MABS 2012, 4, 532-541. [CrossRef] [PubMed]
73. Reski, R.; Parsons, J.; Decker, E.L. Moss-made pharmaceuticals: From bench to bedside. Plant Biotechnol. J. 2015, 13, 1191-1198. [CrossRef] [PubMed]
74. Niederkrüger, H.; Dabrowska-Schlepp, P.; Schaaf, A. Suspension culture of plant cells under phototrophic conditions. In Industrial Scale Suspension Culture of Living Cells; Meyer, H.P., Schmidhalter, D.R., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2014; pp. 259-292.
75. Anterola, A.; Shanle, E.; Perroud, P.F.; Quatrano, R. Production of taxa-4(5), 11(12)-diene by transgenic Physcomitrella patens. Transgenic Res. 2009, 18, 655-660. [CrossRef] [PubMed]
76. Orellana-Escobedo, L.; Rosales-Mendoza, S.; Romero-Maldonado, A.; Parsons, J.; Decker, E.L.; Monreal-Escalante, E.; Moreno-Fierros, L.; Reski, R. An Env-derived multi-epitope HIV chimeric protein produced in the moss Physcomitrella patens is immunogenic in mice. Plant Cell Rep. 2015, 34, 425-433. [CrossRef] [PubMed]
77. Rubio-Infante, N.; Govea-Alonso, D.O.; Alpuche-Solís, Á.G.; García-Hernández, A.L.; Soria-Guerra, R.E.; Paz-Maldonado, L.M.; Ilhuicatzi-Alvarado, D.; Varona-Santos, J.T.; Verdín-Terán, L.; Korban, S. S.; et al. Chloroplast-derived C4V3 polypeptide from the human immunodeficiency virus (HIV) is orally immunogenic in mice. Plant Mol. Biol. 2012, 78, 337-349. [CrossRef] [PubMed]
78. Markou, G.; Nerantzis, E. Microalgae for high-value compounds and biofuels production: A review with focus on cultivation under stress conditions. Biotechnol. Adv. 2013, 31, 1532-1542. [CrossRef] [PubMed]
79. Cox, K.M.; Sterling, J.D.; Regan, J.T.; Gasdaska, J.R.; Frantz, K.K.; Peele, C.G.; Black, A.; Passmore, D.; Moldovan-Loomis, C.; Srinivasan, M. et al. Glycan optimization of a human monoclonal antibody in the aquatic plant Lemna minor. Nat. Biotechnol. 2006, 24, 1591-1597. [CrossRef] [PubMed]
80. Qin, S.; Lin, H.; Jiang, P. Advances in genetic engineering of marine algae. Biotechnol. Adv. 2012, 30, 1602-1613. [CrossRef] [PubMed]
81. Mathieu-Rivet, E.; Kiefer-Meyer, M.-C.; Vanier, G.; Ovide, C.; Burel, C.; Lerouge, P.; Bardor, M. Protein N-glycosylation in eukaryotic microalgae and its impact on the production of nuclear expressed biopharmaceuticals. Front. Plant Sci. 2014, 5. [CrossRef] [PubMed]
82. Lu, Y.; Oyler, G.A. Green algae as a platform to express therapeutic proteins. Discov. Med. 2009, 8, 28-30. [PubMed]
83. Gong, Y.; Hu, H.; Gao, Y.; Xu, X.; Gao, H. Microalgae as platforms for production of recombinant proteins and valuable compounds: Progress and prospects. J. Ind. Microbiol. Biotechnol. 2011, 38, 1879-1890. [CrossRef] [PubMed]
84. Rasala, B.A.; Mayfield, S.P. The microalga Chlamydomonasreinhardtii as a platform for the production of human protein therapeutics. Bioeng. Bugs 2011, 2, 50-54. [CrossRef] [PubMed]
85. Teng, C.; Qin, S.; Liu, J.; Yu, D.; Liang, C.; Tseng, C. Transient expression of lacZ in bombarded unicellular green alga Haematococcuspluvialis. J. Appl. Phycol. 2002, 14, 497-500.
86. Jarvis, E.E.; Brown, L.M. Transient expression of firefly luciferase in protoplasts of the green alga Chlorella ellipsoidea. Curr. Genet. 1991, 19, 317-321. [CrossRef]
87. Hawkins, R.L.; Nakamura, M. Expression of human growth hormone by the eukaryotic alga, Chlorella. Curr. Microbiol. 1999, 38, 335-341. [CrossRef] [PubMed]
88. Eichler-Stahlberg, A.; Weisheit, W.; Ruecker, O.; Heitzer, M. Strategies to facilitate transgene expression in Chlamydomonas reinhardtii. Planta 2009, 229, 873-883. [CrossRef] [PubMed]
89. Phoolcharoen, W.; Bhoo, S.; Lai, H.; Ma, J.; Arntzen, C.J.; Chen, Q.; Mason, H.S. Expression of an immunogenic Ebola immune complex in Nicotianabenthamiana. Plant Biotechnol. J. 2011, 9, 807-816. [CrossRef] [PubMed]
90. De Jaeger, G.; Scheffer, S.; Jacobs, A.; Zambre, M.; Zobell, O.; Goossens, A.; Depicker, A.; Angenon, G. Boosting heterologous protein production in transgenic dicotyledonous seeds using Phaseolus vulgaris regulatory sequences. Nat. Biotechnol. 2002, 20, 1265-1268. [CrossRef] [PubMed]
91. Lu, Z.; Lee, K.J.; Shao, Y.; Lee, J.H.; So, Y.; Choo, Y.K.; Oh, D.B.; Hwang, K.A.; Oh, S.H.; Han, Y.S.; Ko, K. Expression of GA733-Fc fusion protein as a vaccine candidate for colorectal cancer in transgenic plants. J. Biomed. Biotechnol. 2012, 364240. [CrossRef] [PubMed]
92. Downing, W.L.; Galpin, J.D.; Clemens, S.; Lauzon, S.M.; Samuels, A.L.; Pidkowich, M.S.; Clarke, A.; Kermode, A.R. Synthesis of enzymatically active human α-L-iduronidase in Arabidopsiscgl (complex glycan-deficient) seeds. Plant Biotechnol. J. 2006, 4, 169-181. [CrossRef] [PubMed]
93. Ou, J.; Guo, Z.; Shi, J.; Wang, X.; Liu, J.; Shi, B.; Guo, F.; Zhang, C.; Yang, D. Transgenic rice endosperm as a bioreactor for molecular pharming. Plant Cell Rep. 2014, 33, 585-594. [CrossRef] [PubMed]
94. Zhong, Q.; Gu, Z.; Glatz, C.E. Extraction of recombinant dog gastric lipase from transgenic corn seed. J. Agric. Food Chem. 2006, 54, 8086-8092. [CrossRef] [PubMed]
95. Huang, N. High-level protein expression system uses self-pollinating crops as hosts. BioProcess Int. 2004, 2, 54-59.
96. Scheller, J.; Leps, M.; Conrad, U. Forcing single-chain variable fragment production in tobacco seeds by fusion to elastin-like polypeptides. Plant Biotechnol. J. 2006, 4, 243-249. [CrossRef] [PubMed]
97. 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. 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. 2006, 4, 511-527. [CrossRef] [PubMed]
98. Khan, I.; Twyman, R.M.; Arcalis, E.; Stoger, E. Using storage organelles for the accumulation and encapsulation of recombinant proteins. Biotechnol. J. 2012, 7, 1099-1108. [CrossRef] [PubMed]
99. Loos, A.; Steinkellner, H. Plant glyco-biotechnology on the way to synthetic biology. Front. Plant Sci. 2014, 5. [CrossRef] [PubMed]
100. Stoger, E.; Fischer, R.; Moloney, M.; Ma, J.K. Plant molecular pharming for the treatment of chronic and infectious diseases. Annu. Rev. Plant Biol. 2014, 65, 743-768. [CrossRef] [PubMed]
101. Moustafa, K.; Makhzoum, A.; Trémouillaux-Guiller, J. Molecular farming on rescue of pharma industry for next generations. Crit. Rev. Biotechnol. 2015, 4, 1-11. [CrossRef] [PubMed]
102. Mari, A.; Ooievaar-de-Heer, P.; Scala, E.; Giani, M.; Pirrotta, L.; Zuidmeer, L.; Bethell, D.; van Ree, R. Evaluation by double-blind placebo-controlled oral challenge of the clinical relevance of IgE antibodies against plant glycans. Allergy 2008, 63, 891-896. [CrossRef] [PubMed]
103. Floss, D.M.; Sack, M.; Arcalis, E.; Stadlmann, J.; Quendler, H.; Rademacher, T.; Stoger, E.; Scheller, J.; Fischer, R.; Conrad, U. Influence of elastin-like peptide fusions on the quantity and quality of a tobacco-derived human immunodeficiency virus-neutralizing antibody. Plant Biotechnol. J. 2009, 7, 899-913. [CrossRef] [PubMed]
104. Strasser, R.; Altmann, F.; Mach, L.; Glössl, J.; Steinkellner, H. Generation of Arabidopsis thaliana plants with complex N-glycans lacking β1,2-linked xylose and core β1,3-linked fucose. FEBS Lett. 2004, 561, 132-136. [CrossRef]
105. Sourrouille, C.; Marquet-Blouin, E.; D’Aoust, M.A.; Kiefer-Meyer, M.C.; Séveno, M.; Pagny-Salehabadi, S.; Bardor, M.; Durambur, G.; Lerouge, P.; Vezina, L. et al. Down-regulated expression of plant-specific glycoepitopes in alfalfa. Plant Biotechnol. J. 2008, 6, 702-721. [CrossRef] [PubMed]
106. Strasser, R.; Stadlmann, J.; Schähs, M.; Stiegler, G.; Quendler, H.; Mach, L.; Glössl, J.; Weterings, K.; Pabst, M.; Steinkellner, H. Generation of glyco-engineered Nicotianabenthamiana for the production of monoclonal antibodies with a homogeneous human-like N-glycan structure. Plant Biotechnol. J. 2008, 6, 392-402. [CrossRef] [PubMed]
107. Wilken, L.R.; Nikolov, Z.L. Recovery and purification of plant-made recombinant proteins. Biotechnol. Adv. 2012, 30, 419-433. [CrossRef] [PubMed]
108. Chen, Q. Expression and purification of pharmaceutical proteins in plants. Biol. Eng. 2008, 1, 291-321. [CrossRef]
109. Caliber Biotherapeutics Homepage. Available online: http://www.caliberbio.com (accessed on 27 November 2015).
110. Holtz, B.R.; Berquist, B.R.; Bennett, L.D.; Kommineni, V.J.M.; Munigunti, R.K.; White, E. L.;Wilkerson, D. C.; Wong, K. I.; Ly, L. H.; Marcel, S. Commercial-scale biotherapeutics manufacturing facility for plant-made pharmaceuticals. Plant Biotechnol. 2015, 13, 1180-1190. [CrossRef] [PubMed]