Skip to main content
PMC home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2004;79(2):125–145. doi: 10.1007/s11240-004-0653-0

Recent developments in the use of transgenic plants for the production of human therapeutics and biopharmaceuticals

Nilesh P Teli 1, Michael P Timko 1
PMCID: PMC7089434  PMID: 32214567

Abstract

In recent years there has been a dramatic increase in the application of plant biotechnology for the production of a variety of commercially valuable simple and complex biological molecules (biologics) for use in human and animal healthcare. Transgenic whole plants and plant cell culture systems have been developed that have the capacity to economically produce large-scale quantities of antibodies and antibody fragments, antigens and/or vaccine epitopes, metabolic enzymes, hormones, (neuro)peptides and a variety of biologically active complexes and secondary metabolites for direct use as therapeutic agents or diagnostic tools in the medical healthcare industry. As the products of genetically modified plants make their way from concept to commercialization the associated risks and acceptance by the public has been become a focal point. In this paper, we summarize the recent advances made in the use of transgenic plants and plant cell cultures as biological factories for the production of human therapeutics and biopharmaceuticals and discuss the long-term potential of `molecular farming' as a low-cost, efficient method for the production of biological materials with demonstrated utility to the pharmaceutical industry or medical community.

Keywords: edible vaccines, molecular farming, plantibodies, secondary metabolites, therapeutic proteins

References

  1. Ap Rees T. Prospects of manipulating plant metabolism. Trends Biotechnol. 1995;13:375–378. [Google Scholar]
  2. Arakawa T, Chong DKX, Slattery CW, Langridge WHR. Improvements in human health through production of human milk proteins in transgenic food plants. Adv. Exp. Med. Biol. 1999;464:149–159. doi: 10.1007/978-1-4615-4729-7_12. [DOI] [PubMed] [Google Scholar]
  3. Arakawa T, Chong DKX, Langridge WHR. Efficacy of a food plant based oral cholera toxin B subunit vaccine. Nature Biotechnol. 1998;16:292–297. doi: 10.1038/nbt0398-292. [DOI] [PubMed] [Google Scholar]
  4. Arakawa T, Yu J, Chong DKX, Hough J, Engen PC, Langridge WHR. A plant-based cholera toxin B subunit – insulin fusion protein protects against the development of autoimmune diabetes. Nature Biotechnol. 1998;16:934–938. doi: 10.1038/nbt1098-934. [DOI] [PubMed] [Google Scholar]
  5. Arntzen CJ, Mason H, Haq T, Shi J. Expression of genes encoding candidate vaccines in transgenic plants. AIDS Res. Hum. Retrov. 1994;10:S67. [Google Scholar]
  6. Artsaenko O, Kettig B, Fiedler U, Conrad U, During K. Potato tubers as a biofactory for recombinant antibodies. Mol. Breed. 1998;4:313–319. [Google Scholar]
  7. Aziz MA, Singh S, Anandkumar P, Bhatnagar R. Expression of protective antigen in transgenic plants: a step towards edible vaccine against anthrax. Biochem. Biophys. Res. Commun. 2002;299:345–351. doi: 10.1016/s0006-291x(02)02625-6. [DOI] [PubMed] [Google Scholar]
  8. Bakker H, Bardor M, Molthoff JW, Gomard VV, Elbers II, Stevens LH, Jordi W, Lommen A, Faye L, Lerouge P, Bosch D. Galactose-extended glycans of antibodies produced by transgenic plants. Proc. Natl. Acad. Sci. USA. 2001;98:2899–2904. doi: 10.1073/pnas.031419998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Baum TJ, Hiatt A, Parrott WA, Pratt LH, Hussey RS. Expression in tobacco of a functional monoclonal antibody specific to stylet of the root-knot nematode. Mol. Plant Microbe Inter. 1996;9:532–532. [Google Scholar]
  10. Beachy RN, Fitchen JH, Hein MB. Use of plant viruses for delivery of vaccine epitopes. Ann. NY Acad. Sci. 1996;792:43–49. doi: 10.1111/j.1749-6632.1996.tb32489.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bevan MW, Flavell RB, Chilton MD. A chimeric antibiotic resistance gene as a selectable marker for plant cell transformation. Nature. 1983;304:184–187. [PubMed] [Google Scholar]
  12. Birch RG. Plant transformation: problems and strategies for practical application. Ann. Rev. Plant Physiol. Plant Mol. Biol. 1997;48:297–326. doi: 10.1146/annurev.arplant.48.1.297. [DOI] [PubMed] [Google Scholar]
  13. Bottger V, Micheel B, Scharte G, Kaiser G, Wolf G, Schmechta H. Monoclonal antibodies to human chorionic gonadotropin (HCG) and their use in two-site binding enzyme immunoassays. Hybridoma. 1993;12:81–91. doi: 10.1089/hyb.1993.12.81. [DOI] [PubMed] [Google Scholar]
  14. Buchanan-Wollaston V. The molecular biology of leaf senescence. J. Exp. Bot. 1997;48:181–199. [Google Scholar]
  15. Cabanes-Macheteau M, Fitchette-Laine AC, Loutelier-Bourhis C, Lange C, Vine ND, Ma JKC, Lerouge P, Faye L. N-glycosylation of a mouse IgG expressed in transgenic tobacco plants. Glycobiology. 1999;9:365–372. doi: 10.1093/glycob/9.4.365. [DOI] [PubMed] [Google Scholar]
  16. Canel C, Lopez-Cardoso MI, Whitmer S, van der Fits L, Pasquali G, van der Heijden R, Hoge JHC, Verpoorte R. Effects of over-expression of strictosidine synthase and tryptophan decarboxylase on alkaloid production by cell cultures of Catharanthus roseus. Planta. 1998;205:414–419. doi: 10.1007/s004250050338. [DOI] [PubMed] [Google Scholar]
  17. Carrillo C, Wigdorovitz A, Oliveros JC, Zamorano PI, Sadir AM, Gomez N, Salinas J, Escribano JM, Borca MV. Protective immune response to foot-and-mouth disease virus with VP1 expressed in transgenic plants. J. Virol. 1998;72:1688–1690. doi: 10.1128/jvi.72.2.1688-1690.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Carter JE, Langridge WHR. Plant-based vaccines for protection against infectious and autoimmune diseases. Crit. Rev. Plant Sci. 2002;21:93–109. [Google Scholar]
  19. Castanon S, Marin MS, Martin-Alonso JM, Boga JA, Casais R, Humara JM, Ordas RJ, Parra F. Immunization with potato plants expressing VP60 protein protects against rabbit hemorrhagic disease virus. J. Virol. 1999;73:4452–4455. doi: 10.1128/jvi.73.5.4452-4455.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Castanon S, Martin-Alonso JM, Marin MS, Boga JA, Alonso P, Parra F, Ordos RJ. The effect of VP60 gene from rabbit hemorrhagic disease virus in potato plants. Plant Sci. 2002;162:87–95. [Google Scholar]
  21. Chadd HE, Chamow SM. Therapeutic antibody expression technology. Curr. Opin. Biotechnol. 2001;12:188–194. doi: 10.1016/s0958-1669(00)00198-1. [DOI] [PubMed] [Google Scholar]
  22. Chong DKX, Langridge WHR. Expression of fulllength bioactive antimicrobial human lactoferrin in potato plants. Transgenic Res. 2000;9:71–78. doi: 10.1023/a:1008977630179. [DOI] [PubMed] [Google Scholar]
  23. Cline M (2003) Plant-made Pharmaceuticals: Overview of Technology and Stewardship. http: //www.cast-science.org/ cast/biotech/aba2003ClineMolly.htm
  24. Collins GB, Shepherd RJ. Engineering Plants for Commercial Products and Applications. New York: New York Academy of Sciences; 1996. p. 183. [Google Scholar]
  25. Comai L. Impact of plant genetic engineering on foods and nutrition. Ann. Rev. Nutr. 1993;13:191–215. doi: 10.1146/annurev.nu.13.070193.001203. [DOI] [PubMed] [Google Scholar]
  26. Conrad U, Fiedler U. Expression of engineered antibodies in plant cells. Plant Mol. Biol. 1994;26:1023–1030. doi: 10.1007/BF00040685. [DOI] [PubMed] [Google Scholar]
  27. Conrad U, Fiedler U. 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. 1998;38:101–109. [PubMed] [Google Scholar]
  28. Cramer CL, Weissenborn DL, Oishi KK, Grabau EA, Bennett S, Ponce E, Grabowski GA, Radin DN. Bioproduction of human enzymes in transgenic tobacco. Ann. NY Acad. Sci. 1996;792:62–71. doi: 10.1111/j.1749-6632.1996.tb32492.x. [DOI] [PubMed] [Google Scholar]
  29. Curtiss RI & Cardineau CA (1990) Oral Immunization by Transgenic Plants, World Patent Organization WO 90/02484
  30. Daniell H, Khan MS, Allison L. Milestones in chloroplast genetic engineering: an environmental friendly era in biotechnology. Trends Plant Sci. 2002;7:84–91. doi: 10.1016/s1360-1385(01)02193-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Daniell H, Muthukumar B, Lee SB. Marker free transgenic plants: engineering the chloroplast genome without the antibiotic resistance genes. Curr. Genet. 2001;39:109–116. doi: 10.1007/s002940100185. [DOI] [PubMed] [Google Scholar]
  32. Daniell H, Streatfield J, Wycoff K. Medical molecular farming: production of antibodies, biopharmaceuticals and edible vaccines in plants. Trends Plant Sci. 2001;6:219–226. doi: 10.1016/S1360-1385(01)01922-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. De Aizpurua HJ, Russell-Jones GJ. Oral vaccination. Identification of classes of proteins that provoke a response upon oral feeding. J. Exp. Med. 1988;167:440–451. doi: 10.1084/jem.167.2.440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. De Neve M, De Loose M, Jacobs A, Van Houdt H, Kaulza B, Weidle U, Van Montagu M, Depicker A. Assembly of an antibody and its derived antibody fragment in Nicotiana and Arabidopsis. Transgenic Res. 1993;2:227–237. doi: 10.1007/BF01977353. [DOI] [PubMed] [Google Scholar]
  35. Doran P. Foreign protein production in plant tissue cultures. Curr. Opin. Biotechnol. 2000;11:199–204. doi: 10.1016/s0958-1669(00)00086-0. [DOI] [PubMed] [Google Scholar]
  36. During K, Hippe S, Kreutzaler F, Schell J. Synthesis and self-assembly of a functional monoclonal antibody in transgenic Nicotiana tobacum. Plant Mol. Biol. 1990;15:281–293. doi: 10.1007/BF00036914. [DOI] [PubMed] [Google Scholar]
  37. Estevez JM, Cantero A, Reindl A, Reichler S, Leon P. 1-deoxy-D-xylulose-5-phosphate synthase, a limiting enzyme for plastidic isoprenoid biosynthesis in plant. J. Biol. Chem. 2001;276:22901–22909. doi: 10.1074/jbc.M100854200. [DOI] [PubMed] [Google Scholar]
  38. Evangelista RL, Kusnadi AR, Howard JA, Nikolov ZL. Process and economic evaluation of the extraction and purification of recombinant glucuronidase from transgenic corn. Biotechnol. Prog. 1998;14:607–614. doi: 10.1021/bp980047c. [DOI] [PubMed] [Google Scholar]
  39. Featherstone C. Vaccine by agriculture. Mol. Med. Today. 1996;2:278–281. doi: 10.1016/1357-4310(96)20020-6. [DOI] [PubMed] [Google Scholar]
  40. 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. [PubMed] [Google Scholar]
  41. Fischer R, Emans N. Molecular farming of pharmaceutical proteins. Transgenic Res. 2000;9:279–299. doi: 10.1023/a:1008975123362. [DOI] [PubMed] [Google Scholar]
  42. Fischer R, Twyman RM, Schillberg S. Production of antibodies in plants and their use for global health. Vaccine. 2003;21:820–825. doi: 10.1016/s0264-410x(02)00607-2. [DOI] [PubMed] [Google Scholar]
  43. Francisco JA, Gawlak SL, Miller M, Bathe J, Russell D, Chace D, Mixan B, Zhao L, Fell HP, Siegall CB. Expression and characterization of bryodin 1 and a bryodin 1-based single-chain immunotoxin from tobacco cell culture. Bioconjugate Chem. 1997;8:708–713. doi: 10.1021/bc970107k. [DOI] [PubMed] [Google Scholar]
  44. Giddings G. Transgenic plants as protein factories. Curr. Opin. Plant Biotechnol. 2001;12:450–454. doi: 10.1016/s0958-1669(00)00244-5. [DOI] [PubMed] [Google Scholar]
  45. Giddings G, Allison G, Brooks D, Carter C. Transgenic plants as factories for biopharmaceuticals. Nature Biotechnol. 2000;18:1151–1155. doi: 10.1038/81132. [DOI] [PubMed] [Google Scholar]
  46. Gil F, Brun A, Wigdorovitz A, Catala R, Martinez-Torrecuadrada JL, Casal I, Salinas J, Borca MV, Escribano JM. High-yield expression of a viral peptide vaccine in transgenic plants. FEBS Lett. 2001;488:13–17. doi: 10.1016/s0014-5793(00)02405-4. [DOI] [PubMed] [Google Scholar]
  47. Goddijn OJM, Pen J. Plants as bioreactors. Trends Biotechnol. 1995;13:379–387. [Google Scholar]
  48. Gomez N, Carrillo C, Salinas J, Parra F, Borca MV, Escribano JM. Expression of immunogenic glycoprotein S polypeptides from transmissible gastroenteritis corona virus in transgenic plants. Virology. 1998;249:352–358. doi: 10.1006/viro.1998.9315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Gomez N, Wigdorovitz A, Castanon S, Gil F, Ordas RJ, Borca MV, Escribano JM. Oral immunogenicity of the plant derived spike protein from swine-transmissible gastroenteritis corona virus. Arch. Virol. 2000;145:1725–1732. doi: 10.1007/s007050070087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Haq TA, Mason HS, Clements JD, Arntzen CJ. Oral immunization with a recombinant bacterial antigen produced in transgenic plants. Science. 1995;268:714–716. doi: 10.1126/science.7732379. [DOI] [PubMed] [Google Scholar]
  51. Hein MB, Tang Y, McLeod DA, Janda KD, Hiatt A. Evaluation of immunoglobulins from plant cells. Biotechnol. Prog. 1991;7:455–461. doi: 10.1021/bp00011a011. [DOI] [PubMed] [Google Scholar]
  52. Herbers K, Sonnewald U. Production of new/modified proteins in transgenic plants. Curr. Opin. Biotechnol. 1999;10:163–168. doi: 10.1016/s0958-1669(99)80029-9. [DOI] [PubMed] [Google Scholar]
  53. Hiatt AC, Cafferkey R, Bowdish K. Production of antibodies in plants. Nature. 1989;342:76–78. doi: 10.1038/342076a0. [DOI] [PubMed] [Google Scholar]
  54. Hiatt AC, Ma JKC. Characterization and applications of antibodies produced in plants. Int. Rev. Immunol. 1993;10:139–152. doi: 10.3109/08830189309061691. [DOI] [PubMed] [Google Scholar]
  55. Hood EE. From green plants to industrial enzymes. Enz. Microb. Technol. 2002;30:279–283. [Google Scholar]
  56. Hood EE, Witcher DR, Maddock S, Meyer T, Baszczynski C, Bailey M, Flynn P, Register J, Marshall L, Bond D, Kulisek E, Kusnadi A, Evangelista R, Nikolov Z, Wooge C, Mehigh RJ, Hernan R, Kappel WK, Ritland D, Li CP, Howard JA. Commercial production of avidin from transgenic maize: characterization of transformant, production, processing, extraction and purification. Mol. Breed. 1997;3:291–306. [Google Scholar]
  57. Hood EE, Woodard SL, Horn ME. Monoclonal antibody manufacturing in trangenic plants – myths and realities. Curr. Opin. Biotechnol. 2002;13:630–635. doi: 10.1016/s0958-1669(02)00351-8. [DOI] [PubMed] [Google Scholar]
  58. Hu S, Shively L, Raubitschek A, Sherman M, Williams LE, Wong JY, Shively JE, Wu AM. Minibody: a novel engineered anti-carcinoembryonic antigen antibody fragment (single-chain Fv-CH3) which exhibits rapid, high-level targeting of xenografts. Cancer Res. 1996;56:3055–3061. [PubMed] [Google Scholar]
  59. Huang Z, Dry I, Webster D, Strugnell R, Wesselingh S. Plant-derived measles virus hemagglutinin protein induces neutralizing antibodies in mice. Vaccine. 2001;19:2163–2171. doi: 10.1016/s0264-410x(00)00390-x. [DOI] [PubMed] [Google Scholar]
  60. Humphreys DP, Glover DJ. Therapeutic antibody production technologies: molecules, applications, expression and purification. Curr. Opin. Drug Discov. Dev. 2001;4:172–185. [PubMed] [Google Scholar]
  61. Jähne A, Becker D, Lorz H. Genetic engineering of cereal crop plants – a review. Euphytica. 1995;85:35–44. [Google Scholar]
  62. Jorgensen RB, Hauser T, Mikkelsen TR, Ostergard H. Transfer of engineered genes from crop to wild plants. Trends Plant Sci. 1996;1:356–358. [Google Scholar]
  63. Kahl G, Winter P. Plant genetic engineering for crop improvement. World J. Microbiol. Biotechnol. 1995;11:449–460. doi: 10.1007/BF00364620. [DOI] [PubMed] [Google Scholar]
  64. Kapusta J, Modelska A, Figlerowicz M, Pniewski T, Letellier M, Lisowa O, Yushibov V, Koprowski H, Plucienniczak A, Legocki AN. A plant-derived vaccine against hepatitis B virus. FASEB J. 1999;13:1796–1799. doi: 10.1096/fasebj.13.13.1796. [DOI] [PubMed] [Google Scholar]
  65. Kathuria S, Sriraman R, Sack M, Pal R, Artsaenko O, Talwar GP, Fischer R, Finnern R. Efficacy of plantproduced recombinant antibodies against hCG. Human Reprod. 2002;17:2054–2061. doi: 10.1093/humrep/17.8.2054. [DOI] [PubMed] [Google Scholar]
  66. Kilpatrick J, Cockburn B, Whitelam G. The expression of recombinant proteins in crop plants. Outlook Agri. 1995;24:207–211. [Google Scholar]
  67. Kishore GM, Somerville CR. Genetic engineering of commercially useful biosynthetic pathways in transgenic plants. Curr. Opin. Biotechnol. 1993;4:152–158. doi: 10.1016/0958-1669(93)90116-e. [DOI] [PubMed] [Google Scholar]
  68. Kong QX, Richter L, Yang YF, Arntzen CJ, Mason HS, Thanavala Y. Oral immunization with hepatitis B surface antigen expressed in transgenic plants. Proc. Natl. Acad. Sci. USA. 2001;98:11539–11544. doi: 10.1073/pnas.191617598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Koprowski H, Yushibov V. The green revolution: plants as heterologous expression vectors. Vaccine. 2001;19:2735–2741. doi: 10.1016/s0264-410x(00)00511-9. [DOI] [PubMed] [Google Scholar]
  70. Korban SS. Targeting and expression of antigenic proteins in transgenic plants for production of edible oral vaccines. In Vitro Cell Dev. Biol. Plants. 2002;38:231–236. doi: 10.1079/IVP2002292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Kumar PA. Plant biotechnology: future perspectives. Defense Sci. J. 2001;51:353–366. [Google Scholar]
  72. Kumagai MH, Turpen TH, Weinzenl N, Della-Cioppa G, Turpen AM, Donson JD, Hilf ME, Grantham GL, Dawson WO, Chow TP, Piatak M, Grill LK. Rapid, highlevel expression of biologically active alpha-trichosanthin in transfected plants by an RNA viral vector. Proc. Natl. Acad. Sci. USA. 1993;90:427–430. doi: 10.1073/pnas.90.2.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Kusnadi AR, Evangelista RL, Hood EE, Howard JA, Nikolov ZL. Processing of transgenic corn seed and its effect on the recovery of recombinant beta-glucuronidase. Biotechnol. Bioeng. 1998;60:44–52. doi: 10.1002/(sici)1097-0290(19981005)60:1<44::aid-bit5>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  74. Langeveld JPM, Brennan FR, Martinez-Torrecuadrada JL, Jones TD, Boshuizen RS, Vela C, Casal JI, Kamstrup S, Dalsgaard K, Meloen RH, Bendig MM, Hamilton WDO. Inactivated recombinant plant virus protects dogs from a lethal challenge with canine parvovirus. Vaccine. 2001;19:3661–3670. doi: 10.1016/s0264-410x(01)00083-4. [DOI] [PubMed] [Google Scholar]
  75. Langridge WHR. Edible vaccines. Sci. Am. 2000;283:66–71. doi: 10.1038/scientificamerican0900-66. [DOI] [PubMed] [Google Scholar]
  76. Larrick JW, Thomas DW. Producing proteins in transgenic plants and animals. Curr. Opin. Biotechnol. 2001;12:411–418. doi: 10.1016/s0958-1669(00)00236-6. [DOI] [PubMed] [Google Scholar]
  77. Larrick JW, Yu L, Naftzger C, Jaiswal S, Wycoff K. Production of secretory IgA antibodies in plants. Biomol. Eng. 2001;18:87–94. doi: 10.1016/s1389-0344(01)00102-2. [DOI] [PubMed] [Google Scholar]
  78. Lauterslager TGM, Florak DEA, van der Wal TJ, Molthoff JW, Langeveld JPM, Bosch D, Boersma WJA, Hilgers LAT. Oral immunization of native and primed animals with transgenic potato tubers expressing LT-B. Vaccine. 2001;19:2749–2755. doi: 10.1016/s0264-410x(00)00513-2. [DOI] [PubMed] [Google Scholar]
  79. Lee JS, Choi SJ, Kang HS, Oh WG, Cho KH, Kwon TH, Kim DH, Jang YS, Yang MS. Establishment of a transgenic tobacco cell-suspension culture system for producing murine granulocyte-macrophage colony stimulating factor. Mol. Cell. 1997;7:783–787. [PubMed] [Google Scholar]
  80. Lessard PA, Kulaveerasingam H, York GM, Strong A, Sinskey AJ. Manipulating gene expression for the metabolic engineering of plants. Metabolic Eng. 2002;4:67–69. doi: 10.1006/mben.2001.0210. [DOI] [PubMed] [Google Scholar]
  81. Ma JKC, Hein MB. Antibody production and engineering in plants. In: Collins GB, Shepherd RJ, editors. Engineering Plants for Commercial Products and Applications. New York: New York Academy of Sciences; 1996. pp. 72–81. [DOI] [PubMed] [Google Scholar]
  82. Ma JKC, Hiatt A, Hein M, Vine MD, Wang F, Stabila P, van Dolleweerd C, Mostov K, Lehner T. Generation and assembly of secretory antibodies in plants. Science. 1995;268:716–719. doi: 10.1126/science.7732380. [DOI] [PubMed] [Google Scholar]
  83. Ma JK, Hikmat B, Wycoff K, Vine M, Chargelegue D, Yu L, Hein M, Lehner T. Characterization of a recombinant plant monoclonal secretary antibody and preventive immunotherapy in humans. Nature Med. 1998;4:601–606. doi: 10.1038/nm0598-601. [DOI] [PubMed] [Google Scholar]
  84. Ma S, Jevnikar AM. Auto antigens produced in plants for oral tolerance therapy of autoimmune diseases. Advances Exp. Med. Biol. 1999;464:179–194. doi: 10.1007/978-1-4615-4729-7_14. [DOI] [PubMed] [Google Scholar]
  85. Ma JKC, Lehner T, Stabila P, Fux CI, Hiatt A. Assembly of monoclonal antibodies with IgG1 and IgA heavy chain domains in transgenic tobacco plants. Eur. J. Immunol. 1994;24:131–138. doi: 10.1002/eji.1830240120. [DOI] [PubMed] [Google Scholar]
  86. Mahmoud SS, Croteau RB. Metabolic engineering of essential oil yield and composition in mint by altering expression of deoxyxylulose phosphate reducto-isomerase and methanofuran synthase. Proc. Natl. Acad. Sci. USA. 2001;98:8915–8920. doi: 10.1073/pnas.141237298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Mason HS. Plant-based vaccines: expression and oral immunogenicity. In Vitro Cell Dev. Biol. 2002;38:237–240. [Google Scholar]
  88. Mason HS, Arntzen CJ. Transgenic plants as vaccine production systems. Trends Biotechnol. 1995;13:388–392. doi: 10.1016/S0167-7799(00)88986-6. [DOI] [PubMed] [Google Scholar]
  89. Mason HS, Ball JM, Shi JJ, Jiang X, Estes MK, Arntzen CJ. Expression of Norwalk virus capsid protein in transgenic tobacco and potato and its oral immunogenicity in mice. Proc. Natl. Acad. Sci. USA. 1996;93:5335–5340. doi: 10.1073/pnas.93.11.5335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Mason HS, Haq TA, Clements JD, Arntzen CJ. Edible vaccine protects mice against E. coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B gene. Vaccine. 1998;16:1336–1343. doi: 10.1016/s0264-410x(98)80020-0. [DOI] [PubMed] [Google Scholar]
  91. Mason HS, Lam DMK, Arntzen CJ. Expression of hepatitis B surface antigen in transgenic plants. Proc. Natl. Acad. Sci. USA. 1992;89:11745–11749. doi: 10.1073/pnas.89.24.11745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Mason HS, Warzecha H, Mor T, Arntzen CJ. Edible plant vaccines: applications for prophylactic and therapeutic molecular medicine. Trends Mol. Med. 2002;8:324–329. doi: 10.1016/s1471-4914(02)02360-2. [DOI] [PubMed] [Google Scholar]
  93. Matsumoto S, Ikura K, Ueda M, Sasaki R. Characterization of a human glycoprotein (erythropoietin) produced in cultured tobacco cells. Plant Mol. Biol. 1995;27:1163–1172. doi: 10.1007/BF00020889. [DOI] [PubMed] [Google Scholar]
  94. May GD, Afza R, Mason HS, Wiecko A, Novak FJ, Arntzen CJ. Generation of transgenic banana (Musa acuminata) plants via Agrobacterium-mediated transformation. Biotechnol. 1995;13:486–492. [Google Scholar]
  95. McCormick AA, Kumagai MH, Hanley K, Turpen TH, Hakim I, Grill LK, Tuse D, Levy S, Levy R. Rapid production of specific vaccines for lymphoma by expression of tumor-derived single-chain Fv epitopes in tobacco plants. Proc. Natl. Acad. Sci. USA. 1999;96:703–708. doi: 10.1073/pnas.96.2.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. McGarvey PB, Hammond J, Dienelt MM, Hooper DC, Fu ZF, Dietzchold B, Koprowski H, Michaels FH. Expression of the rabies virus glycoprotein in transgenic tomatoes. Biotechnology. 1995;13:1484–1487. doi: 10.1038/nbt1295-1484. [DOI] [PubMed] [Google Scholar]
  97. Miflin B. Crop improvement in the 21st century. J. Exp. Bot. 2000;51:1–8. [PubMed] [Google Scholar]
  98. Modelska A, Dietzschold B, Sleysh N, Fu ZF, Steplewski K, Hooper DC, Koprowski H, Yushibov V. Immunization against rabies with plant-derived antigen. Proc. Natl. Acad. Sci. USA. 1998;95:2481–2485. doi: 10.1073/pnas.95.5.2481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Mor TS, Moon YS, Palmer KE, Mason HS. Geminivirus vectors for high-level expression of foreign proteins in plant cells. Biotechnol. Bioeng. 2003;81:430–437. doi: 10.1002/bit.10483. [DOI] [PubMed] [Google Scholar]
  100. Mor TS, Sternfeld M, Soreq J, Arntzen CJ, Mason HS. Expression of recombinant human acetyl cholinesterase in transgenic tomato plants. Biotechnol. Bioeng. 2001;75:259–266. doi: 10.1002/bit.10012. [DOI] [PubMed] [Google Scholar]
  101. Morrow J. Economics in antibody production. Genet. Eng. News. 2002;22:1–39. [Google Scholar]
  102. Muir SR, Collins GJ, Robinson S, Hughes S, Bovy A, De Vos CHR, Van Tunen AJ, Verhoeyen ME. Over expression of petunia chalcone isomerase in tomato results in fruits containing increased levels of flavonols. Nature Biotechnol. 2001;19:470–474. doi: 10.1038/88150. [DOI] [PubMed] [Google Scholar]
  103. Nemchinov LG, Liang TJ, Rifaat MM, Mazyad HM, Hadidi A, Keith JM. Development of a plant-derived subunit vaccine candidate against hepatitis C virus. Arch. Virol. 2000;145:2557–2573. doi: 10.1007/s007050070008. [DOI] [PubMed] [Google Scholar]
  104. Newell CA. Plant transformation technology – developments and applications. Mol. Biotechnol. 2000;16:53–65. doi: 10.1385/MB:16:1:53. [DOI] [PubMed] [Google Scholar]
  105. Okamoto T, Niu R, Matsuo K, Furuhashi M, Ohsawa M, Mizutani S, Suzuki H. Human chorionic gonadotropin beta-core fragment is directly produced by cancer cells. Life Sci. 2001;68:861–872. doi: 10.1016/s0024-3205(00)00986-3. [DOI] [PubMed] [Google Scholar]
  106. Parmenter DL, van Rooijen GJH & Moloney MM (1994) Oleosins as Carriers of the Anti-Coagulant Protein, Hirudin in Brassica Seeds. Abstracts 4th International Congress of Plant Molecular Biology, Amsterdam, The Netherlands
  107. Pauls KP. Plant biotechnology for crop improvement. Biotechnol. Adv. 1995;13:673–693. doi: 10.1016/0734-9750(95)02010-1. [DOI] [PubMed] [Google Scholar]
  108. Perrin Y, Vaquero C, Gerrard I, Sack M, Drossard J, Stoger E, Christou P, Fischer R. Transgenic pea seeds as a bioreactors for the production of a single chain Fv antibody fragment (scFv) antibody used in cancer diagnosis and therapy. Mol. Breed. 2000;6:345–352. [Google Scholar]
  109. Petolino JF, Young S, Hopkins N, Sukhapinda K, Woosley A, Hayes C, Pelcher L. Expression of murine adenosine deaminase (ADA) in transgenic maize. Transgenic Res. 2000;9:1–9. doi: 10.1023/a:1008972101370. [DOI] [PubMed] [Google Scholar]
  110. Ponstein AS, Verwoerd TC, Pen J. Production of enzymes for industrial use. In: Collins GB, Shepherd RJ, editors. Engineering Plants for Commercial Products and Applications. New York: New York Academy of Sciences; 1996. pp. 91–98. [Google Scholar]
  111. Rakoczy-Trojanowska M. Alternative methods of plant transformation – a short review. Cell Mol. Biol. Lett. 2002;7:849–858. [PubMed] [Google Scholar]
  112. Raskin I, Ribnicky DM, Komarnytsky S, Ilic N, Poulev A, Borisjuk N, Brinker A, Moreno DA, Ripoll C, Yakoby N, O'Neal JM, Cornwell T, Pastor I, Fridlender B. Plants and human health in the twenty-first century. Trends Biotechnol. 2002;20:522–531. doi: 10.1016/s0167-7799(02)02080-2. [DOI] [PubMed] [Google Scholar]
  113. Richter LJ, Thanavala Y, Arntzen CJ, Mason HS. Production of hepatitis B surface antigen in transgenic plants for oral immunization. Nature Biotechnol. 2000;18:1167–1171. doi: 10.1038/81153. [DOI] [PubMed] [Google Scholar]
  114. Rohini VK, Rao KS. Transformation of peanut (Arachis hypogea L.) with tobacco chitinase gene: variable response of transformants to leaf spot disease. Plant Sci. 2001;160:889–898. doi: 10.1016/s0168-9452(00)00462-3. [DOI] [PubMed] [Google Scholar]
  115. Ruf S, Hermann M, Berger IJ, Carrer H, Bock R. Stable genetic transformation of tomato plastids and expression of a foreign protein in fruit. Nature Biotechnol. 2001;19:870–875. doi: 10.1038/nbt0901-870. [DOI] [PubMed] [Google Scholar]
  116. Ruggiero F, Exposito JY, Bournat P, Gruber V, Perret S, Comte J, Olagnier B, Garrone R, Theisen M. Triple helix assembly and processing of human collagen produced in transgenic tobacco plants. FEBS Lett. 2000;469:132–136. doi: 10.1016/s0014-5793(00)01259-x. [DOI] [PubMed] [Google Scholar]
  117. Sala F, Manuela Rigano M, Barbante A, Basso B, Walmsley AM, Castiglione S. Vaccine antigen production in transgenic plants: strategies, gene constructs and perspectives. Vaccine. 2003;21:803–808. doi: 10.1016/s0264-410x(02)00603-5. [DOI] [PubMed] [Google Scholar]
  118. Sandhu JS, Krasnyanski SF, Domier LL, Korban SS, Osadjan MD, Buetow DE. Oral immunization of mice with transgenic tomato fruit expressing respiratory syncytial virus-F protein induces a systemic immune response. Transgenic Res. 2000;9:127–135. doi: 10.1023/a:1008979525909. [DOI] [PubMed] [Google Scholar]
  119. Savelyeva N, Munday R, Spellerberg MB, Lomonossoff GP, Stevenson FK. Plant viral genes in DNA idiotypic vaccines activate linked CD4(+) T-cell mediated immunity against B-cell malignancies. Nature Biotechnol. 2001;19:760–764. doi: 10.1038/90816. [DOI] [PubMed] [Google Scholar]
  120. Saxena D, Flores S, Stotzky G. Transgenic plants – insecticidal toxin in root exudates from Bt corn. Nature. 1999;402:480. doi: 10.1038/44997. [DOI] [PubMed] [Google Scholar]
  121. Sharma HC, Crouch JH, Sharma KK, Seetharama N, Hash CT. Applications of biotechnology for crop improvement: prospects and constraints. Plant Sci. 2002;163:381–395. [Google Scholar]
  122. Smart CM. Gene expression during leaf senescence. New Phytol. 1994;126:419–448. doi: 10.1111/j.1469-8137.1994.tb04243.x. [DOI] [PubMed] [Google Scholar]
  123. Smith MD, Glick BR. The production of antibodies in plants: An idea whose time has come. Biotechnol. Adv. 2000;18:85–89. doi: 10.1016/s0734-9750(99)00036-1. [DOI] [PubMed] [Google Scholar]
  124. Staub JM, Garcia B, Graves J, Hajdukiewicz PT, Hunter P, Nehra N, Paradkar V, Schlittler M, Caroll JA, Spatola L, Ward D, Ye GN, Russell DA. High-yield production of human therapeutic protein in tobacco chloroplast. Nature Biotechnol. 2000;18:333–338. doi: 10.1038/73796. [DOI] [PubMed] [Google Scholar]
  125. Stevens LH, Stoopen GM, Elbers IJW, Molthoff JW, Bakker HAC, Lommen A, Bosch D, Jordi W. Effect of climate conditions and plant developmental stage on the stability of antibodies expressed in transgenic tobacco. Plant Physiol. 2000;124:173–182. doi: 10.1104/pp.124.1.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Stoger E, Sack M, Fischer R, Christou P. Plantibodies: applications, advantages and bottlenecks. Curr. Opin. Biotechnol. 2002;13:161–166. doi: 10.1016/s0958-1669(02)00303-8. [DOI] [PubMed] [Google Scholar]
  127. Stoger E, Vaquero C, Torres E, Sack M, Nicholson L, Drossard J, Williams S, Keen D, Perrin Y, Christou P, Fischer R. Cereal crops as viable production and storage systems for pharmaceutical scFv antibodies. Plant Mol. Biol. 2000;42:583–590. doi: 10.1023/a:1006301519427. [DOI] [PubMed] [Google Scholar]
  128. Streatfield SJ, Jilka JM, Hood EE, Turner DD, Bailey MR, Mayor JM, Woodard SL, Beifuss KK, Horn ME, Delany DE, Tizard IR, Howard JA. Plant-based vaccines: unique advantages. Vaccine. 2001;19:2742–2748. doi: 10.1016/S0264-410X(00)00512-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. Tackaberry ES, Dudani AK, Prior F, Tocchi M, Sardana R, Altosaar I, Ganz PR. Development of biopharmaceuticals in plant expression systems: cloning, expression and immunological reactivity of human cytomegalovirus glycoprotein B (UL55) in seeds of transgenic tobacco. Vaccine. 1999;17:3020–3029. doi: 10.1016/s0264-410x(99)00150-4. [DOI] [PubMed] [Google Scholar]
  130. Tacket CO, Mason HS, Losonsky G, Clements JD, Levine MM, Arntzen CJ. Immunogenicity in humans of a recombinant bacterial antigen delivered in a transgenic potato. Nature Med. 1998;4:607–609. doi: 10.1038/nm0598-607. [DOI] [PubMed] [Google Scholar]
  131. Tacket CO, Mason HS, Losonsky G, Estes MK, Levine MM, Arntzen CJ. Human immune responses to a novel Norwalk virus vaccine delivered in transgenic potatoes. J. Infect. Dis. 2000;182:302–305. doi: 10.1086/315653. [DOI] [PubMed] [Google Scholar]
  132. Talwar GP, Singh O, Pal R, Chatterjee N, Sahai P, Dhall K, Kaur J, Das SK, Suri S, Buckshee K, Saraya L, Saxena BN. A vaccine that prevents pregnancy in women. Proc. Natl. Acad. Sci. USA. 1994;91:8532–8536. doi: 10.1073/pnas.91.18.8532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  133. Terashima M, Hashikawa N, Hattori M, Yoshida H. Growth characteristics of rice cell genetically modified for recombinant human alpha(1)-antitrypsin production. Biochem. Eng. J. 2002;12:155–160. doi: 10.1016/s1369-703x(00)00088-7. [DOI] [PubMed] [Google Scholar]
  134. Thanavala Y. Novel approaches to vaccine development against HBV. J. Biotechnol. 1996;44:67–73. doi: 10.1016/0168-1656(95)00117-4. [DOI] [PubMed] [Google Scholar]
  135. Thanavala Y, Yang YF, Lyons P, Mason HS, Arntzen CJ. Immunogenicity of transgenic plant-derived hepatitis-B surface antigen. Proc. Natl. Acad. Sci. USA. 1995;92:3358–3361. doi: 10.1073/pnas.92.8.3358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  136. Timko MP, Cahoon AB. Transgenic plants for the production of human therapeutics. In: Chopra VL, Malik VS, Bhat SR, editors. Applied Plant Biotechnology. New Hampshire, USA: Science Publishers Inc; 1999. pp. 155–180. [Google Scholar]
  137. Tuboly T, Yu W, Bailey A, Degrandis S, Du S, Erickson L, Nagy E. Immunogenicity of porcine transmissible gastroenteritis virus spike protein expressed in plants. Vaccine. 2000;18:2023–2028. doi: 10.1016/s0264-410x(99)00525-3. [DOI] [PubMed] [Google Scholar]
  138. Vandekerckhove J, Van Damme J, Van Lijsebettens M, Botterman I, De Block M, Vandewiele M, De Clercq A, Leemans J, Van Montagu M, Krebbers E. Enkephalins produced in transgenic plants using modified 2S seed storage proteins. Bio/Technol. 1989;7:929–932. [Google Scholar]
  139. van der Fits L, Memelink J. ORCA3, a jasmonateresponsive transcriptional regulator of plant primary and secondary metabolism. Science. 2000;289:295–297. doi: 10.1126/science.289.5477.295. [DOI] [PubMed] [Google Scholar]
  140. Van Lerebeke N, Engler G, Holsters M, Van den Elsacker S, Zaenen I, Schilperoort RA, Schell J. Large plasmid in Agrobacterium tumefaciens essential for crown gall inducing ability. Nature. 1974;252:169–170. doi: 10.1038/252169a0. [DOI] [PubMed] [Google Scholar]
  141. Vaquero C, Sack M, Chandler J, Drossard J, Schuster F, Monecke M, Schillberg S, Fischer R. Transient expression of a tumor-specific single chain fragment and a chimeric antibody in tobacco leaves. Proc. Natl. Acad. Sci. USA. 1999;96:11128–11130. doi: 10.1073/pnas.96.20.11128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  142. Vaquero C, Sack M, Schuster F, Finnern R, Drossard J, Schumann D, Reimann A, Fischer R. A carcinoembryonic antigen-specific diabody produced in tobacco. FASEB J. 2002;16:U161–182. doi: 10.1096/fj.01-0363fje. [DOI] [PubMed] [Google Scholar]
  143. Veronese P, Li X, Niu XM, Weller SC, Bressan RA, Hasegawa PM. Bioengineering of mint crop improvement. Plant Cell Tiss. Org. Cult. 2001;64:133–141. [Google Scholar]
  144. Verpoorte R, Memelink J. Engineering secondary metabolite production in plants. Curr. Opin. Biotechnol. 2002;13:181–187. doi: 10.1016/s0958-1669(02)00308-7. [DOI] [PubMed] [Google Scholar]
  145. Voss A, Nierbach M, Hain R, Hirsch HJ, Liao Y, Kreuzaler F, Fischer R. Reduced virus infectivity in N. tabacum secreting a TMV-specific full size antibody. Mol. Breed. 1995;1:15–26. [Google Scholar]
  146. Walden R, Wingender R. Gene-transfer and plant regeneration techniques. Trends Biotechnol. 1995;13:324–331. [Google Scholar]
  147. Walmsley AM, Arntzen CJ. Plants for delivery of edible vaccines. Curr. Opin. Biotechnol. 2000;11:126–129. doi: 10.1016/s0958-1669(00)00070-7. [DOI] [PubMed] [Google Scholar]
  148. Williams LE, Beatty BG, Beatty JD, Wong JY, Paxton RJ, Shively JE. Estimation of monoclonal antibody-associated 90Y activity needed to achieve certain tumor radiation doses in colorectal cancer patients. Cancer Res. 1990;50:1029s–1030s. [PubMed] [Google Scholar]
  149. Wu AM, Williams LE, Zieran L, Padma A, Sherman M, Bebb GG, Odom-Maryon T, Wong JYC, Shively JE, Raubitschek AA. Anti-carcinoembryonic antigen (CEA) diabody for rapid tumor targeting and imaging. Tumor Targeting. 1999;4:47–58. [Google Scholar]
  150. Xu H, Montoya FU, Wang ZP, Lee JM, Reeves R, Linthicum DS, Magnuson NS. Combined use of regulatory elements within the cDNA to increase the production of a soluble mouse single-chain antibody, scFv, from tobacco cell suspension cultures. Protein Express. Purif. 2002;24:384–394. doi: 10.1006/prep.2001.1580. [DOI] [PubMed] [Google Scholar]
  151. Ye XD, Al-Babili S, Kloti A, Zhang J, Lucca P, Beyer P, Potrykus I. Engineering the provitamin-A (betacarotene) biosynthetic pathway into (carotenoid-free) rice endosperm. Science. 2000;287:303–305. doi: 10.1126/science.287.5451.303. [DOI] [PubMed] [Google Scholar]
  152. Yu J, Langridge WHR. A plant-based multicomponent vaccine protects mice from enteric diseases. Nature Biotechnol. 2001;19:548–552. doi: 10.1038/89297. [DOI] [PubMed] [Google Scholar]
  153. Zambryski P, Joos H, Genetello C, Leemans J, Van Montagu M, Schell J. Ti plasmid vector for the introduction of DNA into plant cells without alteration of their normal regeneration capacity. EMBO J. 1983;2:2143–2150. doi: 10.1002/j.1460-2075.1983.tb01715.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  154. Zeitlin L, Olmsted SS, Moench TR, Co MS, Martinell BJ, Paradkar VM, Russell DR, Queen C, Cone RA, Whaley KJ. A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes. Nature Biotechnol. 1998;16:1361–1364. doi: 10.1038/4344. [DOI] [PubMed] [Google Scholar]
  155. Zhang H, Zhang S, Cheung NK, Ragupathi G, Livingston PO. Antibodies can eradicate cancer micrometastasis. Cancer Res. 1998;58:2844–2849. [PubMed] [Google Scholar]
  156. Zhang ZB, Kornegay ET, Radcliffe JS, Wilson JH, Veit HP. Comparison of phytase from genetically engineered Aspergillus and canola in weaning pig diets. J. Anim. Sci. 2000;78:2868–2878. doi: 10.2527/2000.78112868x. [DOI] [PubMed] [Google Scholar]
  157. Zhu Z, Hughes KW, Huang L, Sun B, Liu C, Li Y, Hou Y, Li X. Expression of human-interferon cDNA in transgenic rice plants. Plant Cell Tiss. Org. Cult. 1994;36:197–204. [Google Scholar]
  158. Ziegler M, Thomas S, Danna K. Accumulation of a thermostable endo-1,4-b-D-glucanase in the apoplast of Arabidopsis thaliana leaves. Mol. Breed. 2000;6:37–46. [Google Scholar]

Articles from Plant Cell, Tissue and Organ Culture are provided here courtesy of Nature Publishing Group

RESOURCES