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Molecular farming of pharmaceutical proteins

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Abstract

Molecular farming is the production of pharmaceutically important and commercially valuable proteins in plants. Its purpose is to provide a safe and inexpensive means for the mass production of recombinant pharmaceutical proteins. Complex mammalian proteins can be produced in transformed plants or transformed plant suspension cells. Plants are suitable for the production of pharmaceutical proteins on a field scale because the expressed proteins are functional and almost indistinguishable from their mammalian counterparts. The breadth of therapeutic proteins produced by plants range from interleukins to recombinant antibodies. Molecular farming in plants has the potential to provide virtually unlimited quantities of recombinant proteins for use as diagnostic and therapeutic tools in health care and the life sciences. Plants produce a large amount of biomass and protein production can be increased using plant suspension cell culture in fermenters, or by the propagation of stably transformed plant lines in the field. Transgenic plants can also produce organs rich in a recombinant protein for its long-term storage. This demonstrates the promise of using transgenic plants as bioreactors for the molecular farming of recombinant therapeutics, including vaccines, diagnostics, such as recombinant antibodies, plasma proteins, cytokines and growth factors.

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References

  • An G (1985) High efficiency transformation of cultured tobacco cells. Plant Physiol 79: 568–570.

    PubMed  Google Scholar 

  • Arakawa T, Chong DK and Langridge WH (1998a) Efficacy of a food plant-based oral cholera toxin B subunit vaccine [published erratum appears in Nat Biotechnol 1998 16: 478]. Nat Biotechnol 16: 292–297.

    PubMed  CAS  Google Scholar 

  • Arakawa T, Yu J, Chong K, Hough J, Engen PC and Langridge WH (1998b) A plant-based cholera toxin B subunit-insulin fusion protein protects against the development of autoimmune diabetes. Nat Biotechnol 16: 934–938.

    PubMed  CAS  Google Scholar 

  • Artsaenko O, Kettig B, Fiedler U, Conrad U and Düring K (1998) Potato tubers as a biofactory for recombinant antibodies. Mol Breeding 4: 313–319.

    CAS  Google Scholar 

  • Artsaenko O, Peisker M, zur Nieden U, Fiedler U, Weiler EW, Müntz K and Conrad U (1995). Expression of a single-chain Fv antibody against abscisic acid creates a wilty phenotype in transgenic tobacco. Plant J 8: 745–750.

    PubMed  CAS  Google Scholar 

  • Baker D and Harkonen W (1990) Regulatory agency concerns in the manufacturing and testing of monoclonal antibodies for therapeutic use. Targeted Diagn Ther 3: 75–98.

    PubMed  CAS  Google Scholar 

  • Bardor M, Faye L and Lerouge P (1999) Analysis of the Nglycosylation of recombinant glycoproteins produced in transgenic plants. Trends Plants Sci 4: 376–380.

    Google Scholar 

  • Barta A, Sommergruber K, Thompson D, Hartmuth K, Matzke M and Matzke A (1986) The expression of a nopaline synthasehuman growth hormone chimaeric gene in transformed tobacco and sunflower callus tissue. Plant Mol Biol 6: 347–357.

    CAS  Google Scholar 

  • Baum TJ, Hiatt A, Parrott WA, Pratt LH and Hussey RS (1996) Expression in tobacco of a functional monoclonal antibody specific to stylet secretions of the root-knot nematode. Mol Plant Microbe In 9: 382–387.

    CAS  Google Scholar 

  • Benvenuto E, Ordas RJ, Tavazza R, Ancora G, Biocca S, Cattaneo A and Galeffi P (1991) 'Phytoantibodies': A general vector for the expression of immunoglobulin domains in transgenic plants. Plant Mol Biol 17: 865–874.

    PubMed  CAS  Google Scholar 

  • Bisaria V and Panda A (1991) Large-scale plant cell culture: methods, applicatons and products. Curr Opin Biotech 2: 370–374.

    PubMed  CAS  Google Scholar 

  • Bookman MA (1998) Biological therapy of ovarian cancer: current directions. Semin Oncol 25: 381–396.

    PubMed  CAS  Google Scholar 

  • Borisjuk NV, Borisjuk LG, Logendra S, Petersen F, Gleba Y and Raskin I (1999) Production of recombinant proteins in plant root exudates. Nat Biotechnol 17: 466–469.

    PubMed  CAS  Google Scholar 

  • Bosch D, Smal J and Krebber E (1994) A trout growth hormone is expressed, correctly folded and partially glycosylated in the leaves but not the seed of transgenic plants. Transgenic Res 3: 304–310.

    CAS  Google Scholar 

  • Bruyns AM, De Jaeger G, De Neve M, De Wilde C, Van Montagu M and Depicker A (1996) Bacterial and plant-produced scFv proteins have similar antigen-binding properties. FEBS Lett 386: 5–10.

    PubMed  CAS  Google Scholar 

  • Cabanes-Macheteau M, Fitchette-Laine AC, Loutelier-Bourhis C, Lange C, Vine N, Ma J, et al. (1999) N-Glycosylation of a mouse IgG expressed in transgenic tobacco plants. Glycobiology 9: 365–372.

    PubMed  CAS  Google Scholar 

  • Carpita N, Sabularse D, Montezinos D and Delmer DP (1979). Determination of the pore size of cell walls of living plant cells. Science 205: 1144–1147.

    CAS  Google Scholar 

  • Carrillo C, Wigdorovitz A, Oliveros JC, Zamorano PI, Sadir AM, Gomez N, et al. (1998) Protective immune response to foot-andmouth disease virus with VP1 expressed in transgenic plants. J Virol 72: 1688–1690.

    PubMed  CAS  Google Scholar 

  • Chan MT, Chang HH, Ho SL, Tong WF and Yu SM (1993) Agrobacterium-mediated production of transgenic rice plants expressing a chimeric alpha-amylase promoter/beta-glucuronidase gene. Plant Mol Biol 22: 491–506.

    PubMed  CAS  Google Scholar 

  • Chen MH, Liu LF, Chen YR, Wu HK and Yu SM (1994) Expression of alpha-amylases, carbohydrate metabolism, and autophagy in cultured rice cells is coordinately regulated by sugar nutrient. Plant J 6: 625–636.

    PubMed  CAS  Google Scholar 

  • Chintalacharuvu KR and Morrison SL (1997) Production of secretory immunoglobulin A by a single mammalian cell. Proc Natl Acad Sci USA 94: 6364–6368.

    PubMed  CAS  Google Scholar 

  • Christou P (1993) Particle gun-mediated transformation. Curr Opin Biotech 4: 135–141.

    CAS  Google Scholar 

  • Christou P (1996) Transformation technology. Trends Plant Sci 1: 423–431.

    Google Scholar 

  • Conrad U and Fiedler U (1998). 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 38: 101–109.

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Cramer CL, Weissenborn DL, Oishi KK, Grabau EA, Bennett S, Ponce E, Grabowski GA, and Radin DN (1996) Bioproduction of human enzymes in transgenic tobacco. Ann N Y Acad Sci. 792: 62–71.

    PubMed  CAS  Google Scholar 

  • Dalsgaard K, Uttenthal A, Jones TD, Xu F, Merryweather A, Hamilton WD, Langeveld JP, Boshuizen RS, Kamstrup S, Lomonossoff GP, Porta C, Vela C, Casal JI, Meloen RH and Rodgers PB (1997) Plant-derived vaccine protects target animals against a viral disease. Nat Biotechnol 15: 248–252.

    PubMed  CAS  Google Scholar 

  • Daniell T and Edwards R (1995) Changes in protein methylation associated with the elicitation response in cell cultures of alfalfa (Medicago sativa L.). FEBS Lett 360: 57–61.

    PubMed  CAS  Google Scholar 

  • De Jaeger G, Buys E, Eeckhout D, De Wilde C, Jacobs A, Kapila J, Angenon G, Van Montagu M, Gerats T and Depicker A (1998) High level accumulation of single-chain variable fragments in the cytosol of transgenic Petunia hybrida. Eur J Biochem 259: 1–10.

    Google Scholar 

  • De Neve M, De Loose M, Jacobs A, Van Houdt H, Kaluza B, Weidle U, Van Montagu M and Depicker A (1993). Assembly of an antibody and its derived antibody fragment in Nicotiana and Arabidopsis. Transgenic Res 2: 227–237.

    PubMed  CAS  Google Scholar 

  • De Wilde C, De Neve M, De Rycke R, Bruyns AM, De Jaeger G, Van Montagu M, Depicker A and Engler G (1996) Intact antigen-binding MAK33 antibody and Fab fragment accumulate in intercellular spaces of Arabidopsis thaliana. Plant Sci 114: 233–241.

    CAS  Google Scholar 

  • De Zoeten GA, Penswick JR, Horisberger MA, Ahl P, Schultze M and Hohn T (1989) The expression, localization, and effect of a human interferon in plants. Virology 172: 213–222.

    PubMed  CAS  Google Scholar 

  • Desikan R, Hancock JT, Neill SJ, Coffey MJ and Jones OT (1996) Elicitor-induced generation of active oxygen in suspension cultures of Arabidopsis thaliana. Biochem Soc Trans 24: 199S.

    Google Scholar 

  • Dieryck W, Pagnier J, Poyart C, Marden MC, Gruber V, Bournat P, et al. (1997) Human haemoglobin from transgenic tobacco [letter]. Nature 386: 29–30.

    PubMed  CAS  Google Scholar 

  • Düring K, Hippe S, Kreuzaler F and Schell J (1990) Synthesis and selfassembly of a functional monoclonal antibody in transgenic Nicotiana tabacum. Plant Mol Biol 15: 281–293.

    PubMed  Google Scholar 

  • Echelard Y (1996) Recombinant protein production in transgenic animals. Curr Opin Biotech 7: 536–540.

    PubMed  CAS  Google Scholar 

  • Ehsani P, Khabiri A and Domansky NN (1997) Polypeptides of hepatitis B surface antigen produced in transgenic potato. Gene 190: 107–111.

    PubMed  CAS  Google Scholar 

  • Fahrner RL, Blank GS, and Zapata GA (1999) Expanded bed protein A affinity chromatography of a recombinant humanized monoclonal antibody: Process development, operation, and comparison with a packed bed method. J Biotechnol 75: 273–280.

    PubMed  CAS  Google Scholar 

  • Fecker L F, Kaufmann A, Commandeur U, Commandeur J, Koenig R and Burgermeister W (1996). Expression of single-chain antibody fragments (scFv) specific for beet necrotic yellow vein virus coat protein or 25kDa protein in Escherichia coli and Nicotiana benthamiana. Plant Mol Biol 32: 979–986.

    PubMed  CAS  Google Scholar 

  • Fecker LF, Koenig R and Obermeier C (1997) Nicotiana benthamiana plants expressing beet necrotic yellow vein virus (BNYVV) coat protein-specific scFv are partially protected against the establishment of the virus in the early stages of infection and its pathogenic effects in the late stages of infection. Arch Virol 142: 1857–1863.

    PubMed  CAS  Google Scholar 

  • Fiedler U and Conrad U (1995) High-level production and long-term storage of engineered antibodies in transgenic tobacco seeds. Bio/Technol 13: 1090–1093.

    CAS  Google Scholar 

  • Fiedler U, Philips J, Artsaenko O and Conrad U (1997) Optimisation of scFv antibody production in transgenic plants. Immunotechnology 3: 205–216.

    PubMed  CAS  Google Scholar 

  • Firek S, Draper J, Owen MR, Gandecha A, Cockburn B and Whitelam GC (1993a) Secretion of a functional single-chain Fv protein in transgenic tobacco plants and cell suspension cultures [published erratum appears in Plant Mol Biol 1994 Mar; 24(5): 833]. Plant Mol Biol 23: 861–870.

    PubMed  CAS  Google Scholar 

  • Firek S, Draper J, Owen MRL, Gandecha A, Cockburn B and Whitelam GC (1993b) Secretion of a functional single-chain Fv protein in transgenic tobacco plants and cell suspension cultures. Plant Mol Biol 23: 861–870.

    PubMed  CAS  Google Scholar 

  • Fischer R, Drossard J, Commandeur U, Schillberg S and Emans N (1999a) Toward molecular farming in the future: Moving from diagnostic protein and antibody production in microbes to plants. Biotechnol Appl Biochem 30: 101–108.

    PubMed  CAS  Google Scholar 

  • Fischer R, Emans N, Schuster F, Hellwig S and Drossard J (1999b) Toward molecular farming in the future: Using plant cell suspension cultures as bioreactors. Biotechnol Appl Biochem. 30: 113–116.

    PubMed  CAS  Google Scholar 

  • Fischer R, Liao Y-C and Drossard J (1999c) Affinity-purification of a TMV-specific recombinant full-size antibody from a transgenic tobacco suspension culture. J Immunol Meth 226: 1–10.

    CAS  Google Scholar 

  • Fischer R, Schumann D, Zimmermann S, Drossard J, Sack M and Schillberg S (1999d) Expression and characterization of bispecific single chain Fv fragments produced in transgenic plants. European J Biochem 262: 810–816.

    CAS  Google Scholar 

  • Francisco JA, Gawlak SL, Miller M, Bathe J, Russell D, Chace D, et al. (1997) Expression and characterization of bryodin 1 and a bryodin 1-based single-chain immunotoxin from tobacco cell culture. Bioconjug Chem 8: 708–713.

    PubMed  CAS  Google Scholar 

  • Franconi R, Roggero P, Pirazzi P, Arias FJ, Desiderio A, Bitti O, et al. (1999) Functional expression in bacteria and plants of an scFv antibody fragment against tospoviruses. Immunotechnology 4: 189–201.

    PubMed  CAS  Google Scholar 

  • Franken E, Teuschel U and Hain R (1997) Recombinant proteins from transgenic plants. Curr Opin Biotech 8: 411–416.

    PubMed  CAS  Google Scholar 

  • Gallie D 1998. Controlling gene expression in transgenics. Curr Opin Plant Biol 1: 166–172.

    PubMed  CAS  Google Scholar 

  • Gerstmayer B, Hoffmann M, Altenschmidt U and Wels W (1997) Costimulation of T-cell proliferation by a chimeric B7-antibody fusion protein. Cancer Immunol Immunother 45: 156–158.

    PubMed  CAS  Google Scholar 

  • Goossens A, Van Montagu M and Angenon G (1999) Cointroduction of an antisense gene for an endogenous seed storage protein can increase expression of a transgene in Arabidopsis thaliana seeds. FEBS Lett 456: 160–164.

    PubMed  CAS  Google Scholar 

  • Haq TA, Mason HS, Clements JD and Arntzen CJ (1995) Oral immunization with a recombinant bacterial antigen produced in transgenic plants. Science 268: 714–716.

    PubMed  CAS  Google Scholar 

  • Hendy S, Chen ZC, Barker H, Santa Cruz S, Chapman S, Torrance L, Cockburn W and Whitelam GC (1999) Rapid production of single-chain Fv fragments in plants using a potato virus X episomal vector. J Immunol Meth 231: 137–146.

    CAS  Google Scholar 

  • Hiatt A (1990) Antibodies produced in plants. Nature 344: 469–470.

    PubMed  CAS  Google Scholar 

  • Hiatt A, Cafferkey R and Bowdish K (1989) Production of antibodies in transgenic plants. Nature 342: 76–78.

    PubMed  CAS  Google Scholar 

  • Hiatt A and Ma JK (1993) Characterization and applications of antibodies produced in plants. Int Rev Immunol 10: 139–152.

    PubMed  CAS  Google Scholar 

  • Hiatt A, Tang Y, Weiser W and Hein MB (1992) Assembly of antibodies and mutagenized variants in transgenic plants and plant cell cultures. Genet Eng 14: 49–64.

    CAS  Google Scholar 

  • Hiatt AC (1991) Production of monoclonal antibody in plants. Transplant Proc 23: 147–151.

    PubMed  CAS  Google Scholar 

  • Hiei Y, Komari T and Kubo T (1997) Transformation of rice mediated by Agrobacterium tumefaciens. Plant Mol Biol 35: 205–218.

    PubMed  CAS  Google Scholar 

  • Hiei Y, Ohta S, Komari T and Kumashiro T (1994) Efficient transformation of rice (Oryza sativa L.) mediated by Agrobacterium and sequence analysis of the boundaries of the T-DNA. Plant J 6: 271–282.

    PubMed  CAS  Google Scholar 

  • Higo K, Saito Y and Higo H (1993) Expression of a chemically synthesized gene for human epidermal growth factor under the control of cauliflower mosaic virus 35S promoter in transgenic tobacco. Biosci Biotech Biochem 57: 1477–1481.

    CAS  Google Scholar 

  • Hoehl U, Upmeier B and Barz W (1988) Growth and nicotinate biotransformation in batch cultured and airlift fermenter grown soybean cell suspension cultures. Appl Microbiol Biote 28: 319–323.

    CAS  Google Scholar 

  • Hogue RS, Lee JM and An G (1990) Production of a foreign protein product with genetically modified plant cells. Enzyme Microb Technol 12: 533–538.

    PubMed  CAS  Google Scholar 

  • Hood E, Witcher D, Maddock S, Meyer T, Baszczynski C, Bailey M, et al. (1997) Commercial production of Avidin from transgenic maize: characterization of transformant, production, processing, extraction and purification. Mol Breed 3: 291–306.

    CAS  Google Scholar 

  • Hood EE, Kusnadi A, Nikolov Z and Howard JA (1999) Molecular farming of industrial proteins from transgenic maize. Adv Exp Med Biol 464: 127–147.

    PubMed  CAS  Google Scholar 

  • Hooker BS, Lee JM and An G (1990) Cultivation of plant cells in a stirred tank reactor. Biotechnol Bioeng 35: 296–304.

    Google Scholar 

  • Horsch R, Fry JE, Hoffman N, Eicholtz D, Rogers S and Fraley R (1985) A simple and general method for transferring genes into plants. Science 227: 1229–1231.

    CAS  Google Scholar 

  • Johnson J, Lin T and Lomonossoff G (1997) Presentation of heterologous peptides on plant viruses-genetics, structure and function. Ann Rev Phytopathol 35: 67–86.

    CAS  Google Scholar 

  • Kapila J, De Rycke R, van Montagu M and Angenon G (1996) An Agrobacterium mediated transient gene expression system for intact leaves. Plant Sci 122: 101–108.

    Google Scholar 

  • Kapusta J, Modelska A, Figlerowicz M, Pniewski T, Letellier M, Lisowa O, Yusibov V, Koprowski H, Plucienniczak A and Legocki AB (1999) A plant-derived edible vaccine against hepatitis B virus. FASEB J 13: 1796–1799.

    PubMed  CAS  Google Scholar 

  • Khoudi H, Laberge S, Ferullo JM, Bazin R, Darveau A, Castonguay Y, Allard G, Lemieux R and Vezina LP (1999) Production of a diagnostic monoclonal antibody in perennial alfalfa plants. Biotechnol Bioeng 64: 135–143.

    PubMed  CAS  Google Scholar 

  • Kieran PM, MacLoughlin PF and Malone DM (1997) Plant cell suspension cultures: some engineering considerations. J Biotechnol 59: 39–52.

    PubMed  CAS  Google Scholar 

  • Koehler G and Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256: 495–497.

    CAS  Google Scholar 

  • Koncz C and Schell J (1986) The promoter of TL-DNA gene 5 controls the tissue specific expression of chimeric genes carried by a novel type of Agrobacterium binary vector. Mol Gen Genet 204: 383–396.

    CAS  Google Scholar 

  • Kumagai MH, Donson J, della-Cioppa G and Grill LK (2000) Rapid, high-level expression of glycosylated rice alpha-amylase in transfected plants by an RNA viral vector. Gene 245: 169–174.

    PubMed  CAS  Google Scholar 

  • Kusnadi AR, Hood EE, Witcher DR, Howard JA and Nikolov ZL (1998) Production and purification of two recombinant proteins from transgenic corn. Biotechnol Prog 14: 149–155.

    PubMed  CAS  Google Scholar 

  • Kusnadi AR, Nikolov ZL and Howard JA (1997) Production of recombinant proteins in transgenic plants: Practical considerations. Biotechnol Bioeng 56: 473–484.

    CAS  Google Scholar 

  • Larrick JW, Yu L, Chen J, Jaiswal S and Wycoff K (1998) Production of antibodies in transgenic plants. Res Immunol 149: 603–608.

    PubMed  CAS  Google Scholar 

  • Le Gall F, Bove JM and Garnier M (1998) Engineering of a singlechain variable-fragment (scFv) antibody specific for the stolbur phytoplasma (Mollicute) and its expression in Escherichia coli and tobacco plants. Appl Environ Microbiol 64: 4566–4572.

    PubMed  CAS  Google Scholar 

  • Lee JS, Choi SJ, Kang HS, Oh WG, Cho KH, Kwon TH, et al. (1997) Establishment of a transgenic tobacco cell suspension culture system for producing murine granulocyte-macrophage colony stimulating factor. Mol Cell 7: 783–787.

    CAS  Google Scholar 

  • Leite A, Kemper E, da Silva M, Luchessi A, Siloto R, Bonaccorsi E, et al. (2000) Expression of correctly processed human growth hormone in seeds of transgenic tobacco plants. Mol Breeding 6: 47–53.

    CAS  Google Scholar 

  • Lindsey K and Jones MGK (1987) Transient gene expression in electroporated protoplasts and intact cells of sugar beet. Plant Mol Biol 10: 43–52.

    CAS  Google Scholar 

  • Long R (1984) Edible tobacco protein. Crops and Soils Magazine. Feb.: 13–15.

  • Ma J and Hein M (1995a) Immunotherpeuic potential of antibodies produced in plants. Trends Biotechnol 13: 522–527.

    PubMed  CAS  Google Scholar 

  • Ma J and Hein M (1995b) Plant antibodies for Immunotherapy. Plant Physiol 109: 341–346.

    PubMed  CAS  Google Scholar 

  • Ma JK, Hiatt A, Hein M, Vine ND, Wang F, Stabila P, et al. (1995) Generation and assembly of secretory antibodies in plants. Science 268: 716–719.

    PubMed  CAS  Google Scholar 

  • Ma JK, Hikmat BY, Wycoff K, Vine ND, Chargelegue D, Yu L, et al. (1998) Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat Med 4: 601–606.

    PubMed  CAS  Google Scholar 

  • Ma JK and Vine ND (1999) Plant expression systems for the production of vaccines. Curr Top Microbiol Immunol 236: 275–292.

    PubMed  CAS  Google Scholar 

  • Ma JKC, Lehner T, Stabila P, Fux CI and Hiatt A (1994) Assembly of monoclonal antibodies with IgG1 and IgA heavy chain domains in transgenic tobacco plants. Eur J Immunol 24: 131–138.

    PubMed  CAS  Google Scholar 

  • Ma SW, Zhao DL, Yin ZQ, Mukherjee R, Singh B, Qin HY, et al. (1997) Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance. Nat Med 3: 793–796.

    PubMed  CAS  Google Scholar 

  • Magnuson NS, Linzmaier PM, Reeves R, An G, HayGlass K and Lee JM (1998) Secretion of biologically active human interleukin-2 and interleukin-4 from genetically modified tobacco cells in suspension culture. Protein Expr Purif 13: 45–52.

    PubMed  CAS  Google Scholar 

  • Mariani M and L Tarditi (1992) Validating the preparation of clinical monoclonal antibodies. Bio/Technology 10: 394–396.

    PubMed  CAS  Google Scholar 

  • Mason HS and CJ Arntzen (1995) Transgenic plants as vaccine production systems. Trends Biotechnol 13: 388–392.

    PubMed  CAS  Google Scholar 

  • Mason HS, Ball JM, Shi JJ, Jiang X, Estes MK and Arntzen CJ (1996) Expression of Norwalk virus capsid protein in transgenic tobacco and potato and its oral immunogenicity in mice. Proc Natl Acad Sci USA 93: 5335–5340.

    PubMed  CAS  Google Scholar 

  • Mason HS, Haq TA, Clements JD and Arntzen CJ (1998) Edible vaccine protects mice against Escherichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B gene. Vaccine 16: 1336–1343.

    PubMed  CAS  Google Scholar 

  • Mason HS, Lam DM and Arntzen CJ (1992) Expression of hepatitis B surface antigen in transgenic plants. Proc Natl Acad Sci USA 89: 11745–11749.

    PubMed  CAS  Google Scholar 

  • Matsumoto S, Ikura K, Ueda M and Sasaki R (1995) Characterisation of a human glycoprotein (erythropoetin) produced in cultured tobacco cells. Plant Mol Biol 27: 1163–1172.

    PubMed  CAS  Google Scholar 

  • McConnell SJ, Dinh T, Le MH, Brown SJ, Becherer K, Blumeyer K, et al. (1998) Isolation of erythropoietin receptor agonist peptides using evolved phage libraries. Biol Chem 379: 1279–1286.

    PubMed  CAS  Google Scholar 

  • McCormick AA, Kumagai MH, Hanley K, Turpen TH, Hakim I, Grill LK, et al. (1999) 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.

    PubMed  CAS  Google Scholar 

  • McGarvey PB, Hammond J, Dienelt MM, Hooper DC, Fu ZF, Dietzschold B, et al. (1995) Expression of the rabies virus glycoprotein in transgenic tomatoes. Bio/Technology 13: 1484–1487.

    PubMed  CAS  Google Scholar 

  • Miele L (1997) Plants as bioreactors for pharmaceuticals: regulatory considerations. Trends Biotechnol 15: 45–50.

    PubMed  CAS  Google Scholar 

  • Modelska A, Dietzschold B, Sleysh N, Fu ZF, Steplewski K, Hooper DC, Koprowski H and Yusibov V (1998) Immunization against rabies with plant-derived antigen. Proc Natl Acad Sci USA 95: 2481–2485.

    PubMed  CAS  Google Scholar 

  • Moloney MM and Holbrook LA (1997) Subcellular targeting and purification of recombinant proteins in plant production systems. Biotechnol Genet Eng Rev 14: 321–336.

    PubMed  CAS  Google Scholar 

  • Mu JH, Chua NH and Ross EM (1997) Expression of human muscarinic cholinergic receptors in tobacco. Plant Mol Biol 34: 357–362.

    PubMed  CAS  Google Scholar 

  • Murano G (1997) FDA perspective on specifications for biotechnology products – from IND to PLA. Dev Biol Stand 91: 3–13.

    PubMed  CAS  Google Scholar 

  • Murray A, Sekowski M, Spencer DI, Denton G and Price MR (1997) Purification of monoclonal antibodies by epitope and mimotope affinity chromatography. J Chromatogr A 782: 49–54.

    PubMed  CAS  Google Scholar 

  • Nagata T, Nemoto Y and Seiichiro H (1992) Tobacco BY-2 cell line as the ‘HeLa’ cell in the cell biology of higher plants. Int Rev Cytol 132: 1–30.

    CAS  Google Scholar 

  • Nilsson J, Stahl S, Lundeberg J, Uhlen M and Nygren PA (1997) Affinity fusion strategies for detection, purification, and immobilization of recombinant proteins. Protein Expr Purif 11: 1–16.

    PubMed  CAS  Google Scholar 

  • Owen M, Gandecha A, Cockburn B and Whitelam G (1992) Synthesis of a functional anti-phytochrome single-chain Fv protein in transgenic tobacco. Bio/Technology 10: 790–794.

    PubMed  CAS  Google Scholar 

  • Parmenter DL, Boothe JG, van Rooijen GJ, Yeung EC and Moloney MM (1995) Production of biologically active hirudin in plant seeds using oleosin partitioning. Plant Mol Biol 29: 1167–1180.

    PubMed  CAS  Google Scholar 

  • Phillips J, Artsaencko O, Fiedler U, Horstmann C, Mock HP, Müntz K and Conrad U (1997) Seed-specific immunomodulation of abscisic acid activity induces a developmental switch. EMBO J 16: 4489–4496.

    PubMed  CAS  Google Scholar 

  • Porceddu A, Falorni A, Ferradini N, Cosentino A, Calcinaro F, Faleri C, et al. (1999) Transgenic plants expressing human glutamic acid decarboxylase (GAD65), a mojor autoantigen in insulin-dependent diabetes mellitus. Mol Breeding 5: 553–560.

    CAS  Google Scholar 

  • Porta C and Lomonossoff GP (1996) Use of viral replicons for the expression of genes in plants. Mol Biotech 5: 209–221.

    CAS  Google Scholar 

  • Porta C, Spall VE, Lin T, Johnson JE and Lomonossoff GP (1996) The development of cowpea mosaic virus as a potential source of novel vaccines. Intervirology 39: 79–84.

    PubMed  CAS  Google Scholar 

  • Schillberg S, Zimmermann S, Findlay K and R Fischer Plasma membrane display of anti-viral single chain Fv fragments confers resistance to tobacco mosaic virus. Mol. Breeding (in press).

  • Schillberg S, Zimmermann S, Voss A and Fischer R (1999) Apoplastic and cytosolic expression of full-size antibodies and antibody fragments in Nicotiana tabacum. Transgenic Res 8: 255–263.

    PubMed  CAS  Google Scholar 

  • Scholthof H, Scholthof K and Jackson A (1996) Plant virus gene vectors for transient expression of foreign proteins in plants. Annu Rev Phytopathol 34: 299–323.

    PubMed  CAS  Google Scholar 

  • Schouten A, Roosien J, de Boer JM, Wilmink A, Rosso MN, Bosch D, Stiekema WJ, Gommers FJ, Bakker J and Schots A (1997) Improving scFv antibody expression levels in the plant cytosol. FEBS Lett 415: 235–241.

    PubMed  CAS  Google Scholar 

  • Schouten A, Roosien J, van ngelen FA, de Jong GAM, Borst-Vrenssen AWM, Zilverentant JF, et al. (1996) The C-terminal KDEL sequence increases the expression level of a single-chain antibody designed to be targeted to both cytosol and the secretory pathway in transgenic tobacco. Plant Mol Biol 30: 781–793.

    PubMed  CAS  Google Scholar 

  • Seki M, Ohzora C, Takeda M and Furusaki S (1997) Taxol (Paclitaxel) production using free and immobilized cells of taxus cuspidata. Biotechnol Bioengng 53: 214–219.

    CAS  Google Scholar 

  • Sheen S (1983) Biomass and chemical composition of tobacco plants under high density growth. Beitr Tabakforsch Int 12: 35–42.

    CAS  Google Scholar 

  • Shen WH and Hohn B (1995) Vectors based on maize streak virus can replicate to high copy numbers in maize plants. J Gen Virol 76: 965–969.

    PubMed  CAS  Google Scholar 

  • Shin SU, Wright A and Morrison SL (1993) Hybrid antibodies. Int Rev Immunol 10: 177–186.

    PubMed  CAS  Google Scholar 

  • Sijmons PC, Dekker BMM, Schrammeijer B, Verwoerd TC, van den Elzen PJM and Hoekema A (1990) Production of correctly processed human serum albumin in transgenic plants. Bio/Technol 8: 217–221.

    CAS  Google Scholar 

  • Skerra A (1993) Bacterial expression of immunoglobulin fragments. Curr Opin Biotech 5: 256–262.

    CAS  Google Scholar 

  • Staub J, Garcia B, Graves J, Hajdukiewicz P, Hunter P, Nehra N, Paradkar V, Schlittler M, Carroll J, Spatola L, Ward D, Ye G and Russell D (2000) High-yield production of a human therapeutic protein in tobacco chloroplasts. Nature Biotechnol 18: 333–338.

    CAS  Google Scholar 

  • Stöger E, Vaquero C, Torres E, Sack M, Nicholson L, Drossard J, Williams S, Keen D, Perrin Y, Christou P and Fischer R (2000) Cereal crops as viable production and storage systems for pharmaceutical scFv antibodies. Plant Mol Biol 42: 583–590.

    PubMed  Google Scholar 

  • Tackaberry ES, Dudani AK, Prior F, Tocchi M, Sardana R, Altosaar I and Ganz PR (1999) Development of biopharmaceuticals in plant expression systems: cloning, expression and immun ological reactivity of human cytomegalovirus glycoprotein B (UL55) in seeds of transgenic tobacco. Vaccine 17: 3020–3029.

    PubMed  CAS  Google Scholar 

  • Tacket CO, Mason HS, Losonsky G, Clements JD, Levine MM and Arntzen CJ (1998) Immunogenicity in humans of a recombinant bacterial antigen delivered in a transgenic potato. Nat Med 4: 607–609.

    PubMed  CAS  Google Scholar 

  • Taticek RA, Lee CWT and Shukler ML (1994) Large scale insect and plant cell culture. Curr Opin Biotech 5: 165–174.

    PubMed  CAS  Google Scholar 

  • Tavladoraki P, Benvenuto E, Trinca S, De Martinis D, Cattaneo A and Galeffi P (1993) Transgenic plants expressing a functional single-chain Fv antibody are specifically protected from virus attack. Nature 366: 469–472.

    PubMed  CAS  Google Scholar 

  • Terashima M, Murai Y, Kawamura M, Nakanishi S, Stoltz T, Chen L, Drohan W, Rodriguez RL and Katoh S (1999) Production of functional human alpha 1-antitrypsin by plant cell culture. Appl Microbiol Biotechnol 52: 516–523.

    PubMed  CAS  Google Scholar 

  • Torres E, Vaquero C, Nicholson L, Sack M, Stöger E, Drossard J, et al. (1999) Rice cell culture as an alternative production system for functional diagnostic and therapeutic antibodies. Transgenic Res 8: 441–449.

    PubMed  CAS  Google Scholar 

  • Turpen TH, Reinl SJ, Charoenvit Y, Hoffman SL, Fallarme V and Grill LK (1995) Malarial epitopes expressed on the surface of recombinant tobacco mosaic virus. Bio/Technology 13: 53–57.

    PubMed  CAS  Google Scholar 

  • Van Der Heijden R, Verpoorte R and Ten Hoopen HJG (1989) Cell and tissue cultures of Catharanthus-Roseus LG Don a literature survey. Plant Cell Tissue & Organ Culture 18: 231–280.

    Google Scholar 

  • van Engelen FA, Schouten A, Molthoff JW, Roosien J, Salinas J, Dirkse WG, et al. (1994) Coordinate expression of antibody subunit genes yields high levels of functional antibodies in roots of transgenic tobacco. Plant Mol Biol 26: 1701–1710.

    PubMed  CAS  Google Scholar 

  • Vaquero C, Sack M, Chandler J, Drossard J, Schuster F, Schillberg S, et al. (1999) Transient expression of a tumor-specific single chain fragment and a chimeric antibody in tobacco leaves. Proc Natl Acad Sci 96: 11128–11133.

    PubMed  CAS  Google Scholar 

  • Verch T, Lewandowski D and Fischer R (1999) Expression of a single chain antibody in plants using a viral vector (submitted).

  • Verch T, Yusibov V and Koprowski H (1998) Expression and assembly of a full-length monoclonal antibody in plants using a plant virus vector. J Immunol Meth 220: 69–75.

    CAS  Google Scholar 

  • Verwoerd TC, van Paridon PA, van Ooyen AJJ, van Lent JWM, Hoekema A and Pen J (1995) Stable accumulation of Aspergillus niger phytase in transgenic tobacco leaves. Plant Physiol 109: 1199–1205.

    PubMed  CAS  Google Scholar 

  • Voss A, Niersbach M, Hain R, Hirsch H, Liao Y, Kreuzaler F, et al. (1995) Reduced virus infectivity in N. tabacum secreting a TMVspecific full size antibody. Mol Breeding 1: 39–50.

    CAS  Google Scholar 

  • Walmsley A and Arntzen C (2000) Plants for delivery of edible vaccines. Curr Opin Biotech 11: 126–129.

    PubMed  CAS  Google Scholar 

  • Walsh G (1998) Pharmaceuticals, biologics and biopharmaceuticals. In: Biopharmaceuticals: Biochemistry and Biotechnology, (pp. 1–35) Wiley, Chichester, UK.

    Google Scholar 

  • Whitelam GC, Cockburn B, Gandecha AR and Owen MR (1993) Heterologous protein production in transgenic plants. Biotechnol Genet Eng Rev 11: 1–29.

    PubMed  CAS  Google Scholar 

  • Whitelam GC, Cockburn W and Owen MR (1994) Antibody production in transgenic plants. Biochem Soc Trans 22: 940–944.

    PubMed  CAS  Google Scholar 

  • Whitelam GC, aG W (1996) Antibody expression in transgenic plants. Trends Plant Sci 1: 268–271.

    Google Scholar 

  • Wigdorovitz A, Carrillo C, Dus Santos MJ, Trono K, Peralta A, Gomez MC, et al. (1999) Induction of a protective antibody response to foot and mouth disease virus in mice following oral or parenteral immunization with alfalfa transgenic plants expressing the viral structural protein VP1. Virology 255: 347–353.

    PubMed  CAS  Google Scholar 

  • Winter G, Griffiths AD, Hawkins RE and Hoogenboom HR (1994) Making antibodies by phage display technology. Annu Rev Immunol 12: 433–455.

    PubMed  CAS  Google Scholar 

  • Winter G and Milstein C (1991) Man-made antibodies. Nature 349: 293–299.

    PubMed  CAS  Google Scholar 

  • Witcher D, Hood E, Peterson D, Bailey M, Marchall L, Bond D, et al. (1998) Commercial production of b-glucuronidase (GUS): a model system for the production of proteins in plants. Mol Breeding 4: 301–312.

    CAS  Google Scholar 

  • Worn A, Auf Der Maur A, Escher D, Honegger A, Barberis A and Plückthun A (2000) Correlation between in vitro stability and in vivo performance of anti-GCN4 intrabodies as cytoplasmic inhibitors. J Biol Chem 275: 2795–2803.

    PubMed  CAS  Google Scholar 

  • Yusibov V, Modelska A, Steplewski K, Agadjanyan M, Weiner D, Hooper DC, et al. (1997) Antigens produced in plants by infection with chimeric plant viruses immunize against rabies virus and HIV-1. Proc Natl Acad Sci USA 94: 5784–5788.

    PubMed  CAS  Google Scholar 

  • Zeitlin L, Olmsted SS, Moench TR, Co MS, Martinell BJ, Paradkar VM, et al. (1998) A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes. Nat Biotechnol 16: 1361–1364.

    PubMed  CAS  Google Scholar 

  • Zhong G-Y, Peterson D, Delaney D, Bailey M, Witcher D, Register J, et al. (1999) Commercial production of Aprotinin in transgenic maize seeds. Mol Breeding 5: 345–356.

    CAS  Google Scholar 

  • Zhu Z, Hughes K, Huang L, Sun B, Liu C, Li Y, et al. (1994) Expression of human alpha-interferon in plants. Virology 172: 213–222.

    Google Scholar 

  • Ziegler M, Thomas S and Danna K (2000) Accumulation of a thermostable endo-1,4-b-D-glucanase in the apoplast of Arabidopsis thaliana leaves. Mol Breeding 6: 37–46.

    CAS  Google Scholar 

  • Zimmermann S, Schillberg S, Liao YC and Fischer R (1998) Intracellular expression of TMV-specific single-chain Fv fragments leads to improved virus resistance in Nicotiana tabacum. Mol Breeding 4: 369–379.

    CAS  Google Scholar 

  • Zwick M, Shen J and Scott J (1998) Phage-displayed peptide libraries. Curr Opin Biotech 9: 427–436.

    PubMed  CAS  Google Scholar 

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  1. Institut für Biologie I (Botanik/Molekulargenetik), RWTH Aachen, Worringerweg 1, D-52074, Aachen, Germany

    Rainer Fischer

  2. Fraunhofer Department for Molecular Biotechnology, IUCT, Grafschaft, Auf dem Aberg 1, D-57392, Schmallenberg, Germany

    Rainer Fischer

  3. Institut für Biologie I (Botanik/Molekulargenetik), RWTH Aachen, Worringerweg 1, D-52074, Aachen, Germany

    Neil Emans

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Fischer, R., Emans, N. Molecular farming of pharmaceutical proteins. Transgenic Res 9, 279–299 (2000). https://doi.org/10.1023/A:1008975123362

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