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Transgenic plants as factories for biopharmaceuticals

Abstract

Plants have considerable potential for the production of biopharmaceutical proteins and peptides because they are easily transformed and provide a cheap source of protein. Several biotechnology companies are now actively developing, field testing, and patenting plant expression systems, while clinical trials are proceeding on the first biopharmaceuticals derived from them. One transgenic plant-derived biopharmaceutical, hirudin, is now being commercially produced in Canada for the first time. Product purification is potentially an expensive process, and various methods are currently being developed to overcome this problem, including oleosin-fusion technology, which allows extraction with oil bodies. In some cases, delivery of a biopharmaceutical product by direct ingestion of the modified plant potentially removes the need for purification. Such biopharmaceuticals and edible vaccines can be stored and distributed as seeds, tubers, or fruits, making immunization programs in developing countries cheaper and potentially easier to administer. Some of the most expensive biopharmaceuticals of restricted availability, such as glucocerebrosidase, could become much cheaper and more plentiful through production in transgenic plants.

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References

  1. Ma, J.K.C. & Vine, N.D. Plant expression systems for the production of vaccines. Curr. Topics Microbiol. Immunol. 236, 275–292 (1999).

    CAS  Google Scholar 

  2. Ganz, P.R. et al. Expression of human blood proteins in transgenic plants: the cytokine GM-CSF as a model protein. In Transgenic plants: a production system for industrial and pharmaceutical proteins. (eds Owen, M.R.L. & Pen, J). 281–297 (John Wiley & Sons, London, UK; 1996).

    Google Scholar 

  3. Pen, J. Comparison of host systems for the production of recombinant proteins. In Transgenic plants: a production system for industrial and pharmaceutical proteins. (eds Owen, M.R.L. & Pen, J.) 149–167 (John Wiley & Sons, London, UK; 1996).

    Google Scholar 

  4. Whitelam, G.C. The production of recombinant proteins in plants. J. Sci. Food Agric. 68, 1–9 (1995).

    Article  CAS  Google Scholar 

  5. Moloney, M.M. “Molecular farming” in plants: achievements and prospects. Biotechnol. Eng. 9, 3–9 (1995).

    Google Scholar 

  6. Parmenter, D.L. et al. Production of biologically active hirudin in plant seeds using oleosin partitioning. Plant Mol. Biol. 29, 1167–1180 (1995).

    Article  CAS  Google Scholar 

  7. Kusnadi, A., Nikolov, Z.L. & Howard, J.A. Production of recombinant proteins in transgenic plants: practical considerations. Biotechnol. Bioeng. 56, 473–484 (1997).

    Article  CAS  Google Scholar 

  8. Ma, J.K.C. & Hein, M.B. Antibody production and engineering in plants, In Engineering plants for commercial products and applications. (eds Collins, G.B. & Sheperd, R.J.) 72–81 (New York Academy of Sciences, NY; 1996).

    Google Scholar 

  9. Smith, M.D. & Glick, B.R. The production of antibodies in plants. Biotechnol. Adv. 18, 85–89 (2000).

    Article  CAS  Google Scholar 

  10. Cabanes-Macheteau, M. et al. N-glycosylation of a mouse IgG expressed in transgenic tobacco plants. Glycobiology 9, 365–372 (1999).

    Article  CAS  Google Scholar 

  11. Conrad, U., Fiedler, U., Artsaenko, O. & Phillips, J. High-level and stable accumulation of single-chain Fv antibodies in plant storage organs. J. Plant Physiol. 152, 708–711 (1998).

    Article  CAS  Google Scholar 

  12. Sijmons, P.C. et al. Production of correctly processed human serum albumin in transgenic plants. Bio/Technology 8, 217–221 (1990).

    CAS  PubMed  Google Scholar 

  13. Cramer, C.L. et al. Bioproduction of human enzymes in transgenic tobacco. In Engineering plants for commercial products and applications. (eds Collins, G.B. & Sheperd, R.J.) 62–71 (New York Academy Of Sciences, NY; 1996).

    Google Scholar 

  14. Doran, P.M. Foreign protein production in plant tissue cultures Curr. Opin. Biotechnol. 11, 199–204 (2000).

    Article  CAS  Google Scholar 

  15. Tacket, C.O. & Mason, H.S. A review of oral vaccination with transgenic vegetables. Microbes Infect. 1, 777–783 (1999).

    Article  CAS  Google Scholar 

  16. Della-Cioppa, G. & Grill, L.K. Production of novel compounds in higher plants by transfection with RNA viral vectors. In Engineering plants for commercial products and applications. (eds Collins, G.B. & Sheperd, R.J.) 57–61 (New York Academy of Sciences, NY; 1996).

    Google Scholar 

  17. Hiatt, A.C., Cafferkey, R. & Bowdish, K. Production of antibodies in transgenic plants. Nature 342, 76–78 (1989).

    Article  CAS  Google Scholar 

  18. Kumagai, M.H. et al. Rapid, high-level expression of biologically active alpha-trichosanthin in transfected plants by an RNA viral vector. Proc. Natl. Acad. Sci. USA 90, 427–430 (1993).

    Article  CAS  Google Scholar 

  19. McCormick A.A. et al. Rapid production of specific vaccines for lymphoma by expression of the tumor-derived single-chain Fv epitopes in tobacco plants. Proc. Natl. Acad. Sci. USA 96, 703–708 (1999).

    Article  CAS  Google Scholar 

  20. Boothe, J.G., Parmenter, D.L. & Saponja J.A. Molecular farming in plants: oilseeds as vehicles for the production of pharmaceutical proteins. Drug Develop. Res. 42, 172–181 (1997).

    Article  CAS  Google Scholar 

  21. Hamamoto, H. et al. A new tobacco mosaic virus vector and its use for the systematic production of angiotensin-I-converting enzyme inhibitor in transgenic tobacco and tomato. Bio/Technology 11, 930–932 (1993).

    CAS  PubMed  Google Scholar 

  22. McGarvey, P.B. et al. Expression of the rabies virus glycoprotein in transgenic tomatoes. Bio/Technology 13, 1484–1487 (1995).

    CAS  PubMed  Google Scholar 

  23. Johnson, E. Edible plant vaccines. Nat. Biotechnol. 14,1532–1533 (1996).

    Article  CAS  Google Scholar 

  24. Dalsgaard, K. et al. Plant-derived vaccine protects target animals against a viral disease. Nat. Biotechnol. 15, 248–252 (1997).

    Article  CAS  Google Scholar 

  25. Goddijn, O.J.M. & Pen, J. Plants as bioreactors. Trends Biotechnol. 13, 379–387 (1995).

    Article  CAS  Google Scholar 

  26. Vandekerckhove, J. et al. Enkephalines produced in transgenic plants using modified 2S storage proteins. Bio/Technology 7, 929–932 (1989).

    CAS  Google Scholar 

  27. Chaudhary, S., Parmenter, D.L. & Moloney, M.M. Transgenic Brassica carinata as a vehicle for the production of recombinant proteins in seeds. Plant Cell Reports 17,195–200 (1998).

    Article  CAS  Google Scholar 

  28. Tacket, C.O. et al. Immunogenicity in humans of a recombinant bacterial antigen delivered in a transgenic potato. Nat. Med. 4, 607–609 (1998).

    Article  CAS  Google Scholar 

  29. Ma, S.W. et al. Transgenic plants expressing autoantigens fed to induce oral immune tolerance. Nat. Med. 3, 793–517 (1997).

    Article  CAS  Google Scholar 

  30. Dixon, R.A. & Arntzen, C.J. Transgenic plant technology is entering the era of metabolic engineering. Trends Biotechnol. 15, 441–444 (1997).

    Article  CAS  Google Scholar 

  31. Artsaenko, O. et al. Potato tubers as a biofactory for recombinant antibodies. Mol. Breeding 4, 313–319 (1998).

    Article  CAS  Google Scholar 

  32. Burkhardt, P.K. et al. Transgenic rice (Oryza sativa) endosperm expressing daffodil (Narcissus pseudonarcissus) phytoene synthase accumulates phytoene, a key intermediate of provitamin a biosynthesis. Plant J. 11, 1071–1078 (1997).

    Article  CAS  Google Scholar 

  33. Stoger, E. et al. Cereal crops as viable production and storage systems for pharmaceutical scFv antibodies. Plant Mol. Biol. 42, 583–590 (2000).

    Article  CAS  Google Scholar 

  34. Zhong, G.Y. et al. Commercial production of aprotinin in transgenic maize seeds. Mol. Breeding 5, 345–356 (1999).

    Article  CAS  Google Scholar 

  35. Mushegian, A.R. & Shepard, R.J. Genetic elements of plant viruses as tools for genetic engineering. Microbiol. Rev. 59, 548–578 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Beachy, R.N., Fitchen, J.H. & Hein, M.B. Use of plant viruses for delivery of vaccine epitopes, In Engineering plants for commercial products and applications. (eds Collins, G.B. & Sheperd, R.J.) 43–49 (New York Academy of Sciences, NY; 1996).

    Google Scholar 

  37. Turpen, T.H. et al. Malarial epitopes expressed on the surface of recombinant tobacco mosaic virus. Bio/Technology 13, 53–57 (1995).

    CAS  PubMed  Google Scholar 

  38. Brennan, F.R. et al. Chimeric plant virus particles administered nasally or orally induce systemic and mucosal immune responses in mice. J. Virol. 73, 930–938 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Durrani Z. et al. Intranasal immunization with a plant virus expressing a peptide from HIV-1 gp41 stimulates better mucosal and systemic HIV-1-specific IgA and IgG than oral immunization. J. Immunol. Methods 220, 93–103 (1998).

    Article  CAS  Google Scholar 

  40. Ma, J.K.-C. & Hiatt, A. Expressing antibodies in plants for immunotherapy. In Transgenic plants: a production system for industrial and pharmaceutical proteins. (eds Owen, M.R.L. & Pen, P.) 229–243 (John Wiley & Sons, London, UK; 1996).

    Google Scholar 

  41. Cramer, C., Boothe, J.G. & Oishi, K.K. Transgenic plants for therapeutic proteins: linking upstream and downstream strategies. Curr. Topics Microbiol. Immunol. 240, 95–118 (1999).

    CAS  Google Scholar 

  42. Hood, E.E. & Jilka, J.M. Plant-based production of xenogenic proteins. Curr. Opin. Biotechnol. 10, 382–386 (1999).

    Article  CAS  Google Scholar 

  43. Thanavala, Y. et al. Immunogenicity of transgenic plant-derived hepatitis B surface antigen. Proc. Natl. Acad. Sci. USA 92, 3358–3361 (1995).

    Article  CAS  Google Scholar 

  44. Lam, D.M-K., Arntzen, C.J. Anti-viral vaccines expressed in plants. US 05612487 (1997); Arntzen, C.J. & Lam, D.M-K. Vaccines expressed in plants. US 5914123 (1995); Arntzen, C.J. & Lam, D.M-K. Vaccines produced and administered through edible plants. US 5484719 (1996); Arntzen, C.J., Lam, D.M-K, Mason, H.S. Vaccines expressed in plants. US 6034298 (2000).

  45. Richter, L.J., Thanavala, Y., Arntzen, C.J. & Mason, H.S. Production of hepatitis B surface antigen in transgenic plants for oral immunization. Nat. Biotechnol. 18, 1167–1171 (2000).

    Article  CAS  Google Scholar 

  46. Arakawa, T et al. A plant-based cholera toxin B subunit-insulin fusion protein protects against the development of autoimmune diabetes. Nat. Biotechnol. 16, 934–938 (1998).

    Article  CAS  Google Scholar 

  47. Arakawa, T., Chong, D.K.X. & Langridge, W.H.R. Efficacy of a food plant-based oral cholera toxin B subunit vaccine. Nat. Biotechnol. 16, 292–297 (1998).

    Article  CAS  Google Scholar 

  48. Ma, J.K.C. et al. Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat. Med. 4, 1078–8956 (1998).

    Article  Google Scholar 

  49. Fischer, R., Hoffmann, K., Schillberg, S. & Emans, N. Antibody production by molecular farming in plants. J. Biol. Regul. Homeost. Agents 14, 83–92 (2000).

    CAS  PubMed  Google Scholar 

  50. Halling Sorensen, B. et al. Occurrence, fate and effects of pharmaceutical substances in the environment–a review. Chemosphere 36, 357–394 (1998).

    Article  CAS  Google Scholar 

  51. Dieryck W et al. Human haemoglobin from transgenic tobacco. Nature 386, 29–30 (1997).

    Article  CAS  Google Scholar 

  52. Ruggiero, F. et al. Triple helix assembly and processing of human collagen produced in transgenic tobacco plants. FEBS Lett. 469, 132–136 (2000).

    Article  CAS  Google Scholar 

  53. Chakraborty, S., Chakraborty, N., & Datta, A. Increased nutritive value of transgenic potato by expressing a nonallergenic seed albumin gene from Amaranthus hypochondriacus. Proc. Natl. Acad. Sci. USA 97, 3724–2729 (2000).

    Article  CAS  Google Scholar 

  54. Gray, A. J. & Raybould, A. F. Reducing transgene escape routes. Nature 392, 653–654 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

Our thanks to the UK Department of Transport, Environment and the Regions (DETR), who funded this work as part of their program on risk assessment for the release of genetically modified plants.

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Correspondence to Glynis Giddings.

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Giddings, G., Allison, G., Brooks, D. et al. Transgenic plants as factories for biopharmaceuticals. Nat Biotechnol 18, 1151–1155 (2000). https://doi.org/10.1038/81132

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