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Facing the Future with Pharmaceuticals from Plants

  • Rainer Fischer
  • Richard M. Twyman
  • Stephan Hellwig
  • Jürgen Drossard
  • Stefan Schillberg

Plants are the ultimate source of many of today’s pharmaceutical compounds, but most of our protein drugs are derived from animal sources, and are produced either in cultured animal cells or microbes. The biopharmaceutical industry has developed with mammalian cells treated as the gold standard for production, hence the regulations governing biopharmaceutical production have been tailored for these systems.biopharmaceutical production, despite their many potential advantages which include the prospect of inexpensive, large-scale biopharmaceutical production without sacrificing product quality or safety. The first plant-derived pharmaceutical products have now been approved but these represent a tiny proportion of the products in development, products which could have a profound impact on the cost and availability of medicines to those most in need. In this review, we summarize the state-of-the-art in plant-based production systems and discus the development issues which remain to be addressed before plants become an acceptable mainstream production technology.

Keywords

Plant Cell Culture Transgenic Potato Recombinant Antibody Glycan Structure Curr Opin Plant Biol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Bai Y, Glatz CE (2003) Bioprocess considerations for expanded-bed chromato-graphy of crude canola extract: Sample preparation and adsorbent reuse. Bio-technol Bioeng 81: 775-782.CrossRefGoogle Scholar
  2. Bakker H, Bardor M, Molthoff JW, Gomord V, Elbers I, Stevens LH, Jordi W, Lommen A, Faye L, Lerouge P, Bosch D (2001) Galactose-extended glycans of antibodies produced by transgenic plants. Proc Natl Acad Sci USA 98: 2899-2904.CrossRefPubMedGoogle Scholar
  3. Blixt O, Allin K, Pereira L, Datta A, Paulson JC (2002) Efficient chemoenzymatic synthesis of O-linked sialyl oligosaccharides. J Am Chem Soc 124: 5739-5746.CrossRefPubMedGoogle Scholar
  4. CPMP (2002) Points to consider on quality aspects of medicinal products contain-ing active substances produced by stable transgene expression in higher plants (CPMP/BWP/764/02). The European Agency for the Evaluation of Medicinal Products (EMEA).Google Scholar
  5. Decker EL, Reski R (2004) The moss bioreactor. Curr Opin Plant Biol 7: 166-170.CrossRefPubMedGoogle Scholar
  6. Drossard J (2003) Downstream processing of plant-derived recombinant therapeutic proteins. In: Fischer R, Schillberg S (eds) Molecular Farming Plant-made Pharmaceuticals and Technical Proteins. John Wiley & Sons Inc., NY, pp. 217-231.Google Scholar
  7. Fahrner RL, Knudsen HL, Basey CD, Galan W, Feuerhelm D, Vanderlaan M, Blank GS (2001) Industrial purification of pharmaceutical antibodies: Development, operation, and validation of chromatography processes. Biotechnol Genet Eng Rev 18: 301-327.PubMedGoogle Scholar
  8. Faye L, Boulaflous A, Benchabane M, Gomord V, Michaud D (2005) Protein modifications in the plant secretory pathway: current status and practical implications in molecular pharming. Vaccine 23: 1770-1778.CrossRefPubMedGoogle Scholar
  9. FDA (2002) Guidance for industry. Drugs, biologics, and medical devices derived from bioengineered plants for use in humans and animals. Food and Drug Administration.Google Scholar
  10. Fischer R, Schumann D, Zimmermann S, Drossard J, Sack M, Schillberg S (1999) Expression and characterization of bispecific single-chain Fv fragments pro-duced in transgenic plants. Eur J Biochem 262: 810-816.CrossRefPubMedGoogle Scholar
  11. Fischer R, Stoger E, Schillberg S, Christou P, Twyman RM (2004) Plant based production of biopharmaceuticals. Curr Opin Plant Biol 7: 152-158.CrossRefPubMedGoogle Scholar
  12. Gavilondo JV, Larrick JW (2000) Antibody production technology in the millen-nium. Biotechniques 29: 128-145.PubMedGoogle Scholar
  13. Gomord V, Chamberlain P, Jefferis R, Faye L (2005) Biopharmaceutical produc-tion in plants: problems, solutions and opportunities. Trends Biotechnol 23: 559-565.CrossRefPubMedGoogle Scholar
  14. Gomord V, Sourrouille C, Fitchette AC, Bardor M, Pagny S, Lerouge P, Faye L (2004) Production and glycosylation of plant-made pharmaceuticals: The anti-bodies as a challenge. Plant Biotechnol J 2: 83-100.CrossRefPubMedGoogle Scholar
  15. Gottschalk U (2006) Downstream processing in biomanufacturing: Removing economic and technical bottlenecks. Bioforum Europe 10: 28-31.Google Scholar
  16. Hellwig S, Drossard J, Twyman RM, Fischer R (2004) Plant cell cultures for the production of recombinant proteins. Nat Biotechnol 22: 1415-1422.CrossRefPubMedGoogle Scholar
  17. Hiatt A, Cafferkey R, Bowdish K (1989) Production of antibodies in transgenic plants. Nature 342: 76-78.CrossRefPubMedGoogle Scholar
  18. Huang J, Sutliff TD, Wu L, Nandi S, Benge K, Terashima M, Ralston AH, Drohan W, Huang N, Rodriguez RL (2001) Expression and purification of functional human α1-antitrypsin from cultured plant cells. Biotechnol Prog 17: 126-133.CrossRefPubMedGoogle Scholar
  19. Huang J, Wu L, Yalda D, Adkins Y, Kelleher SL, Crane M, Lonnerdal B, Rodri-guez RL, Huang N (2002) Expression of functional recombinant human lysozmye in transgenic rice cell culture. Transgenic Res 11: 229-239.CrossRefPubMedGoogle Scholar
  20. Kapusta J, Modelska A, Figlerowicz M, Pniewski T, Letellier M, Lisowa O, Yusibov V, Koprowski H, Plucienniczak A, Legocki AB (1999) A plant-derived edible vaccine against hepatitis B virus. FASEB J 13: 1796-1799.PubMedGoogle Scholar
  21. Lamphear BJ, Streatfield SJ, Jilka JM, Brooks CA, Barker DK, Turner DD, Delaney DE, Garcia M, Wiggins B, Woodard SL, Hood EE, Tizard IR, Lawhorn B, Howard JA (2002) Delivery of subunit vaccines in maize seed. J Control Release 85: 169-180.CrossRefPubMedGoogle Scholar
  22. Ma JKC, Barros E, Bock R, Christou P, Dale PJ, Dix PJ, Fischer R, Irwin J, Mahoney R, Pezzotti M, Schillberg S, Sparrow P, Stoger E, Twyman RM (2005a) Molecular farming for new drugs and vaccines. Current perspectives on the production of pharmaceuticals in transgenic plants. EMBO Reports 6: 593-599.CrossRefPubMedGoogle Scholar
  23. Ma JKC, Chikwamba R, Dale PJ, Fischer R, Mahoney R, Twyman RM (2005b) Plant-derived pharmaceuticals - The road forward. Trends Plant Sci 10: 580-585.CrossRefPubMedGoogle Scholar
  24. Ma JKC, Drake P, Christou P (2003) The production of recombinant pharmaceutical proteins in plants. Nat Rev Genet 4: 794-805.CrossRefPubMedGoogle Scholar
  25. Ma JK, Hiatt A, Hein M, Vine ND, Wang F, Stabila P, van Dolleweerd C, Mostov K, Lehner T (1995) Generation and assembly of secretory antibodies in plants. Science 268: 716-719.CrossRefPubMedGoogle Scholar
  26. Ma JK, Hikmat BY, Wycoff K, Vine ND, Chargelegue D, Yu L, Hein MB, Lehner T (1998) Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat Med 4: 601-606.CrossRefPubMedGoogle Scholar
  27. McCormick AA, Kumagai MH, Hanley K, Turpen TH, Hakim I, Grill LK, Tuse D, Levy S, Levy R (1999) Rapid production of specific vaccines for lym-phoma by expression of the tumor-derived single-chain Fv epitopes in tobacco plants. Proc Natl Acad Sci USA 96: 703-708.CrossRefPubMedGoogle Scholar
  28. Menkhaus TJ, Bai Y, Zhang C, Nikolov ZL, Glatz CE (2004) Considerations for the recovery of recombinant proteins from plants. Biotechnol Prog 20: 1001-1014.CrossRefPubMedGoogle Scholar
  29. Menkhaus TJ, Glatz CE (2005) Antibody capture from corn endosperm extracts by packed bed and expanded bed adsorption. Biotechnol Prog 21: 473-485.CrossRefPubMedGoogle Scholar
  30. Mora J, Sinclair A, Delmdahl N, Gottschalk U (2006) Disposable membrane chromatography. Performance analysis and economic cost model. BioProcess Int (suppl): 2-6.Google Scholar
  31. Nikolov ZL, Woodard SL (2004) Downstream processing of recombinant proteins from transgenic feedstock. Curr Opin Biotechnol 15: 479-486.CrossRefPubMedGoogle Scholar
  32. Platis D, Labrou NE (2006) Development of an aqueous two-phase partitioning system for fractionating therapeutic proteins from tobacco extract. J Chroma-togr A 1128: 114-124.CrossRefGoogle Scholar
  33. 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 (2002) Plants and human health in the twenty-first century. Trends Biotechnol 20: 522-531.CrossRefPubMedGoogle Scholar
  34. Richter LJ, Thanavala Y, Arntzen CJ, Mason HS (2000) Production of hepatitis B surface antigen in transgenic plants for oral immunization. Nat Biotechnol 18: 1167-1171.CrossRefPubMedGoogle Scholar
  35. Sahai OP, Shuler ML (1984) Multistage continuous culture to examine secondary metabolite formation in plant cells: Phenolics from Nicotiana tabacum. Bio-technol Bioeng 26: 27-36.CrossRefGoogle Scholar
  36. SemBioSys (2006) SemBioSys achieves major insulin milestone. http://www.investor look.com/adminv2/downloads/119/07.17.06%20Insulin%20Accumulation%20 `final.pdf.
  37. Seveno M, Bardor M, Paccalet T, Gomord V, Lerouge P, Faye L (2004) Glyco-protein sialylation in plants? Nat Biotechnol 22: 1351-1352.CrossRefPubMedGoogle Scholar
  38. Shah MM, Fujiyama K, Flynn CR, Joshi L (2003) Sialylated endogenous glyco-conjugates in plant cells. Nat Biotechnol 21: 1470-1471.CrossRefPubMedGoogle Scholar
  39. Shah MM, Fujiyama K, Flynn CR, Joshi L (2004) Glycoprotein sialylation in plants? Reply. Nat Biotechnol 22: 1352-1353.CrossRefGoogle Scholar
  40. Sharp JM, Doran PM (2001) Strategies for enhancing monoclonal antibody accu-mulation in plant cell and organ cultures. Biotechnol Prog 17: 979-992.CrossRefPubMedGoogle Scholar
  41. Sijmons PC, Dekker BMM, Schrammeijer B, Verwoerd TC, Van Den Elzen PJM, Hoekema A (1990) Production of correctly processed human serum albumin in transgenic plants. Bio/Technol 8: 217-221.CrossRefGoogle Scholar
  42. Sriraman R, Bardor M, Sack M, Vaquero C, Faye L, Fischer R, Finnern R, Lerouge P (2004) Recombinant anti-hCG antibodies retained in the endo-plasmic reticulum of transformed plants lack core-xylose and core-α(1,3)-fucose residues. Plant Biotechnol J 2: 279-287.CrossRefPubMedGoogle Scholar
  43. Stoger E, Ma JK, Fischer R, Christou P (2005) Sowing the seeds of success: pharmaceutical proteins from plants. Curr Opin Biotechnol 16: 167-173.CrossRefPubMedGoogle Scholar
  44. Strasser R, Altmann F, Mach L, Glossl J, 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.CrossRefPubMedGoogle Scholar
  45. Tacket CO, Mason HS, Losonsky G, Clements JD, Levine MM, Arntzen CJ (1998) Immunogenicity in humans of a recombinant bacterial-antigen deliv-ered in transgenic potato. Nat Med 4: 607-609.CrossRefPubMedGoogle Scholar
  46. Tacket CO, Mason HS, Losonsky G, Estes MK, Levine MM, Arntzen CJ (2000) Human immune responses to a novel norwalk virus vaccine delivered in transgenic potatoes. J Infect Dis 182: 302-305.CrossRefPubMedGoogle Scholar
  47. Tacket CO, Pasetti MF, Edelman R, Howard JA, Streatfield S (2004) Immuno-genicity of recombinant LT-B delivered orally to humans in transgenic corn. Vaccine 22: 4385-4389.CrossRefPubMedGoogle Scholar
  48. Triguero A, Cabrera G, Cremata JA, Yuen CT, Wheeler J, Ramírez NI (2005) Plant-derived mouse IgG monoclonal antibody fused to KDEL endoplasmic reticulum-retention signal is N-glycosylated homogeneously throughout the plant with mostly high-mannose-type N-glycans. Plant Biotechnol J 3: 449-457.CrossRefPubMedGoogle Scholar
  49. Tsoi BM, Doran PM (2002) Effect of medium properties and additives on antibody stability and accumulation in suspended plant cell cultures. Biotechnol Appl Biochem 35: 171-180.CrossRefPubMedGoogle Scholar
  50. Twyman RM, Schillberg S, Fischer R (2005) Transgenic plants in the biopharma-ceutical market. Expert Opin Emerg Drugs 10: 185-218.CrossRefPubMedGoogle Scholar
  51. Twyman RM, Stoger E, Schillberg S, Christou P, Fischer R (2003) Molecular farming in plants: Host systems and expression technology. Trends Biotechnol 21: 570-578.CrossRefPubMedGoogle Scholar
  52. Xu H, Montoya FU, Wang Z, Lee JM, Reeves R, Linthicum DS, Magnuson NS (2002) 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 Exp Purif 24: 384-394.CrossRefGoogle Scholar
  53. Yano A, Maeda F, Takekoshi M (2004) Transgenic tobacco cells producing the human monoclonal antibody to hepatitis B virus surface antigen. J Med Virol 73: 208-215.CrossRefPubMedGoogle Scholar
  54. Yusibov V, Hooper DC, Spitsin SV, Fleysh N, Kean RB, Mikheeva T, Deka D, Karasev A, Cox S, Randall J, Koprowski H (2002) Expression in plants and immunogenicity of plant virus-based experimental rabies vaccine. Vaccine 20: 3155-3164.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Rainer Fischer
    • 1
  • Richard M. Twyman
    • 2
  • Stephan Hellwig
    • 1
  • Jürgen Drossard
    • 1
  • Stefan Schillberg
    • 1
  1. 1.Fraunhofer Institute for Molecular Biology and Applied EcologyGermany
  2. 2.Department of BiologyUniversity of YorkHeslingtonUK

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