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Transgenic Plants for Therapeutic Proteins: Linking Upstream and Downstream Strategies

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Plant Biotechnology

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 240))

Abstract

With the new knowledge generated through the Human Genome Project and related biomedical research comes a potential revolution in drug development strategies. One of the most direct applications of this knowledge will be highly specialized recombinant protein-based therapeutics. Recombinant drugs such as human erythropoietin (EPO), tissue plasminogen activator (tPA), and CerezymeTM (glucocerebrosidase) are currently on the market and many other recombinant proteins are in various stages of human clinical trials. Commercial production of these proteins utilizes fermentation (primarily E. coli and yeast) and mammalian cell systems (e.g., Chinese hamster ovary cells), the major expression systems adopted by the well established biotechnology companies. However, these expression systems have significant limitations. Bacteria cannot perform the complex posttranslational modifications required for bioactivity of many human proteins and high-level expression often leads to accumulation of insoluble protein aggregates. While mammalian cell cultures perform the required protein modifications, low transgene expression levels, instability of selected cell lines, and the difficulties and high expense of scale-up are often limiting or severely impact cost. Thus, there remains significant opportunity for alternative expression systems that address these limitations and cost issues to compete in the protein therapeutics market. In fact, development of more cost-effective protein bioproduction systems may be critical in translating the discoveries of genomics and medical research into widely available and affordable treatments and cures.

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References

  • Abell BM, Holbrook LA, Abenes M, Murphy DJ, Hills MJ. Moloney MM (1997) Role of the prolinc knot motif in oleosin endoplasmic reticulum topology and oil body targeting. Plant Cell 9:1481–1493

    PubMed  CAS  Google Scholar 

  • Barton NW, Brady RO, Dambrosia JM, Brisaceglie AM, Doppelt SH, Hill SC. Mankin HJ. Murray GJ. Parker RI, Argoi CE. Grewal RP, Yu K-T (1991) Replacement therapy of inherited enzyme deficiency: macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med 324: 1464

    Article  PubMed  CAS  Google Scholar 

  • Bender E. Vogel R. Koller K. Engels J (1990) Synthesis and secretion of hirudin by Strepomyces lividans. Appt Microbiol Biotech 34: 203–207

    Article  CAS  Google Scholar 

  • Benfey PN. Ling R, Chua N-H (1989) The CaMV 35 S enhancer contains at least two domains which can confer different developmental and tissue-specific expression patterns. EMBO.J 8:2195–2202

    PubMed  CAS  Google Scholar 

  • Bosch D. Smal J. 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

    Article  CAS  Google Scholar 

  • Brady RO, Pentchev PG, Gal AE, Hibbert SR. Dekaban AS (1974) Replacement therapy for inherited enzyme deficiency. Use of purified glucocerebrosidase in Gaucher’s disease. N Fngl J Med 291:989–993

    Article  CAS  Google Scholar 

  • Braun PJ, Dennis S, Hofsteenge J, Stone SR (1988) Use of site-directed mutaecnesis io iniestigate the basis for the specificity, of hirudin. Biochemistry 27: 6517–6522

    Article  PubMed  CAS  Google Scholar 

  • Carrington.IC, Freed DD (1990) Cap-independent enhancement of translation by a plant potvcirus 5’ nontranslated region. J Virol 64: 1590–1597

    Google Scholar 

  • Chatrenet B. Chang J (1992) The folding of hirudin adopts a mechanism of trial and error. J Biol Chem 267: 3038–3043

    PubMed  CAS  Google Scholar 

  • Chatrenet B. Chang J (1993) The disulfide folding pathway of hirudin elucidated hv stop go folding experiments. J Biol Chem 268: 20988–20996

    PubMed  CAS  Google Scholar 

  • Chinn AM, Comai L (1996) Gene transcription. In: Owen MRL, Pen J (eds) Transgenic plants: a production system for industrial and pharmaceutical proteins. Wiley, Chichester, pp 27–48

    Google Scholar 

  • Chong DKX, Roberts W, Arakawa T, Illes K, Bagi G, Slattery CW, Landridge WHR (1997) Expression of the human milk protein b-casein in transgenic potato plants. Transgenic Res 6: 289–296

    Article  PubMed  CAS  Google Scholar 

  • Chrispeels MJ, Faye L (1996) The production of recombinant glycoproteins with defined non-immunogenic glycans. In: Owen MRL, Pen J (eds) Transgenic plants: a production system for industrial and pharmaceutical proteins. Wiley, Chichester, pp 99–114

    Google Scholar 

  • Cramer CL, Weissenborn DL, Oishi KK, Grabau EA, Bennett S, Ponce E, Grabowski GA, Radin DN (1996a) Bioproduction of human enzymes in transgenic tobacco. In: Collins GB, Shepherd RJ (eds) Engineering Plants for Commercial Products and Applications. New York Academy of Sciences, New York, pp 62–71

    Google Scholar 

  • Cramer CL, Weissenborn DL, Oishi KK, Radin DN (1996b) High-level production of enzymatically active human lysosomal proteins in transgenic plants. In: Owen MRL, Pen J (eds) Transgenic plants: a production system for industrial and pharmaceutical proteins. Wiley, Chichester, pp 299–310

    Google Scholar 

  • Cramer CL, Weissenborn DL (1997) HMG2 promoter expression system and post-harvest production of gene products in plants and plant cell cultures. US. Patent 5,670,349

    Google Scholar 

  • Darnell J, Lodish H, Baltimore D (1986) Molecular cell biology. Scientific American, New York Denecke J, Botterman J, Deblaere R (1990) Protein secretion in plant cells can occur via a default pathway. Plant Cell 2: 51–59

    Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Dieryck W, Pagnier J, Poyart C, Marden MC, Gruber V, Bournat P, Baudino S, Merot B (1997) Human haemoglobin from transgenic tobacco. Nature 385: 29–30

    Article  Google Scholar 

  • DiFerrante NM, Nicholds BL Jr (1974) Comments on the plasma treatment of the mucopolysaccharidoses. Birth Defects 10: 234–238

    Google Scholar 

  • Fang R-X, Nagy F, Sivasubramanian S, Chua N-H (1989) Multiple cis-regulatory elements for maximal expression of the cauliflower mosaic virus 35S promoter in transgenic plants. Plant Cell 1: 141–150

    PubMed  CAS  Google Scholar 

  • Faye L, Johnson KD, Strum A, Chrispeels MJ (1989) Structure, biosynthesis, and function of asparaginelinked glycans on plant glycoproteins. Plant Physiol 75: 309–314

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Ganz PR, Dudani AK, Tackaberry ES, Sardana R, Sauder C, Cheng X, Altosaar I (1996) Expression of human blood proteins in transgenic plants: the cyokine GM-CSF as a model protein. In: Owen MRL, Pen J (eds) Transgenic plants: a production system for industrial and pharmaceutical proteins. Wiley, Chichester, pp 281–297

    Google Scholar 

  • Grabowski GA, Barton NW, Pastores G, Drambrosia JM, Banerjee TK, McKee MA. Parker C, Schiffmann R, Hill SC, Brady RO (1995) Enzymes therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med 122:33–39

    PubMed  CAS  Google Scholar 

  • Grill LK (1993) Tobacco mosaic virus as a gene expression vector. Agro-Food-Industry Hi-Tech November/December: 20–23

    Google Scholar 

  • Grill LK (1997) Viral-vectored, large scale production of drugs and pharmaceuticals in plants. Presentation at IBCs 3rd Annual International Symposim on Producing the Next Generation of Therapeutics: Exploiting Transgenic Technologies, West Palm Beach, 5–6 Feb

    Google Scholar 

  • Grinnell BW, Walls JD, Gerlitz B (1991) Glycosylation of human protein C affects its secretion, processing, functional activities and activation by thrombin. J Biol Chem 226: 9778–9785

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Harvey RP, Degryse E, Stefani L, Schamber F, Cazenave JP, Courtney M, Tolstoshev P, Lecocq JP (1986) Cloning and expression of cDNA coding for anticoagulant hirudin from blood-sucking leech, Hirudo ntedicinulis. Proc Natl Acad Sci USA 83: 1084–1088

    Article  PubMed  CAS  Google Scholar 

  • Hein MB, Yeo T-C, Wang F, Sturtevant A (1996) Expression of cholera toxin subunits in plants. In: Collins GB, Shepherd RJ (eds) Engineering plants for commercial products and applications. New York Academy of Sciences, New York, pp 50–56

    Google Scholar 

  • Herbers K, Wilke I, Sonnewald U (1995) A thermostable xylanase from Clostridium thernmcellwtt expressed at high levels in the apoplast of transgenic tobacco has no detrimental effects and is easily purified. Biotechnology 13: 63–66

    Article  CAS  Google Scholar 

  • Higo K. Saito Y, 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 Biotechnol Biochem 57: 1477–1481

    Article  PubMed  CAS  Google Scholar 

  • Hills MJ, Watson MD. Murphy DJ (1993) Targeting of oleosins to the oil bodies of oilseed rape. Planta 189:24

    Article  PubMed  CAS  Google Scholar 

  • Horsch RB, Fry JE, Hoffmann NL, Eichholtz D, Rogers SG, Fraley RT (1985) A simple and general method for transferring genes into plants. Science 227: 1229–1231

    Article  CAS  Google Scholar 

  • Jenkins N, Parekh RB, James DC (1996) Getting the glycosylation right: implication for the biotechnology industry. Nat Biotechnol 14: 975–981

    Article  PubMed  CAS  Google Scholar 

  • Kay R, Chan A, Dal M, McPherson J (1987) Duplication of CaMV 35S promoter sequences creates a strong enhancer for plant genes. Science 236: 1299–1302

    Article  PubMed  CAS  Google Scholar 

  • Kakkis ED. Matynia A, Jonas AJ, Neufeld FE (1994) Overexpression of the human lysosomal enzymes a-L-iduronidase in Chinese hamster ovary cells. Prot Express Pur 5:225–232

    Article  CAS  Google Scholar 

  • Kakkis ED, McEntee ME, Schmidtchen A, Neufeld EF, Ward DA, Gompf RE. Kania S. Bedolla C. Chien SE. Schull RM (1996) Long-terni and high-dose trials of enzyme replacement therapy in the canine model of mucopolysaccharidosis I. Biochem Mol Med 58: 156–167

    Article  PubMed  CAS  Google Scholar 

  • Klocking H (1991) Toxicology of hirudin. Sem Thromb Hemostas 17: 126–129

    Article  CAS  Google Scholar 

  • Kühnel B. Holbrook LA. Moloney MM and van Rooijen GJH (1996) Oil bodies of transgenic Brucsica napus as a source of immobilized β-glucuronidase. J Am Oil Chem Soc 73: 1533–1538

    Article  Google Scholar 

  • Kumagai MH. Tupen TH. Weinzattl N. Della-Cioppa G. Turpen AM. Donson.J. Hilf ME. Grantham GL. Dawson WO, Chosv TP. Piatak M.I. Grill LK (1993) Rapid high-level expression of biologically active a-trichosanthin in transfected plants by an RNA viral vector. Proc Natl Acad Sci USA 90, 427–430

    Article  PubMed  CAS  Google Scholar 

  • Lehman ED, Joyce JG, Bailey FT, Markus HZ, Schultz LD, Dunwillei CT, Jacobson MA. Miller WJ (1993) Expression, purification and characterization of multigram amounts of a recombinant hybrid HVI-HV2 hirudin variant expressed in Sacebaronnres cerevisar. Protein Expr Pur 4:247–255

    Article  CAS  Google Scholar 

  • Lindsey’ K (1996) Plant transformation systems. In: Owen MRL. Pen.J (eds) Transgenic plants: a production system for industrial and pharmaceutical proteins. Wiley, Chichester. pp 5–20

    Google Scholar 

  • Loison G. Gindeli A, Bernard S, Nguyen-Juilleret M, Marquet M, Riehl-Bellon N. Carvallo D, Guerra-Santos L, Brown SW. Courtney M, Roitsch C. Lemoin Y (1988) Expression and secretion in Scererisiae of biologically active leech hirudin. Biotechnology 6: 72–77

    Article  CAS  Google Scholar 

  • Lui DTY (1992) Glycoprotein pharmaceuticals scientific and regulatory considerations and the l:nited States Orphan Drug Act. Trends Biotechnol 10: 114–120

    Article  Google Scholar 

  • Ma JK-C. Hiatt A, Vine ND, Wand P. Stabia P, van Dollerweerd C. Mostov K. Lehner T (1995) Generation and assembly of secretory antibodies in plants. Science 208: 716–719

    Article  Google Scholar 

  • Ma S. Zhao D. Yin A, Mukherjee R, Singh B. Qin H. Stiller CR, Jevnikar AM (1997) Transgenic plants expressing autoantigens fed to mice induce oral immune tolerance. Nat Med 3: 793–790

    Article  PubMed  CAS  Google Scholar 

  • Markwardt F. Hauptmann J. Nowak G. Kleben C. Walsmann P (1982) Pharmacological studies on the antithromhotic action of hirudin in experimental animals. Thromb Haemoctasis 47: 226–229

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Matsumoto S. Ikura K. Ueda M. Sasaki R. (1995) Characterization of a human glvcoprotcin (erythropoietin) produced in cultured tobacco cells. Plant Mal Biol 27: 1163–1172

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Moloney MM and van Rooijen GJH (1996) Recombinant proteins via oleosin partitioning. Inform 7: 107–113

    Google Scholar 

  • Moskowitz SM. Dlott B. Chuang PD, Neufeld EF (1992) Cloning and expression of a cDNA encoding the human lysosomal enzyme α-I -iduronidase. FASEB J 6: A77 (abstract)

    Google Scholar 

  • NIH Technology Assessment Panel on Gaucher Disease (1996) Gaucher disease: current issues in diagnosis and treatment. DAMA 275: 548–553

    Google Scholar 

  • Neufeld EF (1991) Lysosomal storage diseases. Anna Rev Biochem 60: 257–280

    Article  CAS  Google Scholar 

  • Neufeld EF. Muenzer J (1989) The mucopolysaccharidoses. In: Scriver CR. Beaudet AL.. Sly WS. Valle D (eds) The metabolic basis of inherited disease 6th edn. McGraw-Hill. Ness York. pp 1565 1587

    Google Scholar 

  • Neufeld EF. Muenzer.J(1995) The mucopolysaccharidoses. In: River CR, Beaudet A1. Sly WS. Valle D (eds) The metabolic and molecular hases of inherited disease 7th edn. McGraw-Hill_ New York. pp 2405–2494

    Google Scholar 

  • Owen MRL. Pen.J (1996) Transgenic plants: a production system for industrial and pharmaceutical proteins. Wiley. Chichester

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Pen J (1996) Comparison of host systems for the production of recombinant proteins. In: Owen MRL, Pen J (eds) A production system for industrial and pharmaceutical proteins. Wiley. Chichester, pp:149–168

    Google Scholar 

  • Pen J, Verwoerd TC, van Paridon PA, Buedeker RF, van den Elzen PJM, Geerse K, van der Klis JD, Versteegh JAJ, van Ooyen AJJ, Hoekema A (1993) Phytase-containing transgenic seed as a novel feed additive for improved phosphorus utilization. Biotechnology 11: 811–814

    Article  CAS  Google Scholar 

  • Roberts GW, James S (1996) Prion diseases: transmission from mad cows? Curr Biol 6: 1247–1249

    Article  PubMed  CAS  Google Scholar 

  • Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C. Fenton JW II (1990) The structure of a complex of recombinant hirudin and human α-thrombin. Science 249: 277

    Article  PubMed  CAS  Google Scholar 

  • Scott HS, Nelson PV, Hopwood JJ, Morris CP (1991) Human a-L-iduronidase: cDNA isolation and expression. Proc Nati Acad Sci USA 88: 9695–9699

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Stone SR, Maraganore JM (1993) Hirudin and hirudin-based peptides. Methods Enzymol 223: 312–336

    Article  PubMed  CAS  Google Scholar 

  • Taylor CB (1997) Comprehending cosuppression. Plant Cell 9: 1245–1249

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Tzen JTC, Huang AHC (1992) Surface structure and properties of plant seed oil bodies. J Cell Biol 117: 327–335

    Article  PubMed  CAS  Google Scholar 

  • Usha R, Rohl JB, Spall VE, Shanks M, Maule AJ, Johnson JE, Lomonossoff GP (1993) Expression of an animal virus antigenic site on the surface of a plant virus particle. Virology 197: 366–374

    Article  PubMed  CAS  Google Scholar 

  • van Rooijen GJH, Moloney MM (1995a) Structural requirements of oleosin domains for the subcellular targeting to the oil body. Plant Physiol 109: 1353–1361

    Article  PubMed  Google Scholar 

  • van Rooijen GJH, Moloney MM (1995b) Plant seed oil-bodies as carriers for foreign proteins. Biotechnology 13: 72–77

    Article  PubMed  Google Scholar 

  • Vandekerckhove J, Van Damme J, Van Lijsebettens M, Botterman J De Block M, Vandewiele M De Clercq A, Leemans J, Van Montagu M, Krebbers E (1989) Enkephalins produced in transgenic plants using modified 2\S seed storage proteins. Biotechnology 7: 929–932

    Article  CAS  Google Scholar 

  • Varki A (1993) Biological roles of oligosaccharides: all of the theories are correct. Glycobiology 3: 97–130

    Article  PubMed  CAS  Google Scholar 

  • Vaughan P (1996) Creutzfeld-Jakob disease-latest unknown in struggle to restore faith in the blood supply. Can Med Assoc J 155: 565–568

    CAS  Google Scholar 

  • Verwoerd TC, Pen J (1996) Phytase produced in transgenic plants for use as a novel feed additive. In: Transgenic plants: a production system for industrial and pharmaceutical proteins. Wiley, Chichester, pp 213–225

    Google Scholar 

  • von Schaewen A, Sturm A, O’Neill J. Chrispeels MJ (1993) Isolation of a mutant Arabidopsis plant that lacks N-acetylglucosaminyltransferase I and is unable to synthesize Golgi-modified complex N-linked glycans. Plant Physiol 102: 1109 - I118

    Article  Google Scholar 

  • Weissenborn DL, Grabau EA, Pedersen K, Oishi KK, Bennett S, Velander W, Cramer CL (1995) Production of human protein C in transgenic tobacco. International Conference on Engineering Plants for Commercial Products and Applications, Lexington KY, October, 1995 (abstract 50)

    Google Scholar 

  • Zhao HG, Li HH, Bach G, Schmidtchen A, Neufeld EF (1996) The molecular basis of San Filippo syndrome type B. Proc Natl Acad Sci USA 12: 6101–6105

    Article  Google Scholar 

  • Zhu Z, Hughes KW, Huang L, Sun B, Lui C, Li Y, Hou Y, Li X (1994) Expression of human a-interferon cDNA in transgenic rice plants. Plant Cell Tissue Org Cult 36: 197–204

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. CropTech Corp., Virginia Tech Corporate Research Center, Blacksburg, VA, 24000, USA

    C. L. Cramer

  2. Department of Plant Pathology. Physiology and Weed Science, Fralin Biotechnology Center, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061-0346, USA

    C. L. Cramer

  3. Sem BioSys Genetics Inc., Suite 204. 609 14th St. N.W., Calgary , Alberta, T2N, Canada

    J. G. Boothe

  4. CropTech Corp., Virginia Tech Corporate Research Center, Blacksburg, VA, 24060, USA

    K. K. Oishi

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  1. C. L. Cramer
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  1. Florist and Nursery Crops Unit, USDA-ARS, USNA, Rm. 238, B-010A, 10300 Baltimore Ave., 20705, Beltsville, MD, USA

    John Hammond Ph.D.

  2. National Biomedical Research Foundation, Georgetown University Medical Center, LR-3, Preclinical Science Building, 3900 Reservoir Road, NW, Washington, DC, 20007, USA

    Peter McGarvey Ph.D.

  3. Biotechnology Foundation Labs., Thomas Jefferson University, Rm. M85, JAH, 1020 Locust Street, 19107, Philadelphia, PA, USA

    Vidaldi Yusibov Ph.D.

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Cramer, C.L., Boothe, J.G., Oishi, K.K. (2000). Transgenic Plants for Therapeutic Proteins: Linking Upstream and Downstream Strategies. In: Hammond, J., McGarvey, P., Yusibov, V. (eds) Plant Biotechnology. Current Topics in Microbiology and Immunology, vol 240. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60234-4_5

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