Transgenic plants as bioreactors for the production of substances of medicinal and veterinary importance


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Abstract

The use of plants as bioreactors has become of a great importance in the modern biotechnology. The transgenic plants are capable of synthesizing of many substances, including valuable pharmaceuticals. Plants possess a number of advantages compared to conventional bioreactors - microorganisms and animal cell cultures. The product safety and lower production costs are among them. One of the promising directions in plant biotechnology is the creation of “edible vaccines, plantibodies and adjuvants” based on recombinant antigens, immunoglobulins and immunoregulatory cytokines. Edible bioreactor plants can be administered as food and feed additives in medicine and veterinary avoiding expensive purification procedures. Interferons have antiviral, antibacterial, antitumor and immunomodulatory activity, and are implicated in the prophylaxis and therapy of diseases of different etiologies. Investigations concerning with obtaining of bioreactor plants synthesizing γ-interferons of mammals and birds are carried out in the laboratory of genetic and cellular engineering of plants St. Petersburg State University. Our recent achievements in the creation of inbreed tobacco line producing bovine γ-interferon are described.

About the authors

Natalia Vladimirovna Saveleva

Lab. UMR

Email: nata.saveljeva@gmail.com
к. б. н., доцент

Mikhail Sergeevich Burlakovskiy

St. Petersburg State University

Email: burmish@yandex.ru
Dept. Of Genetics and Biotechnology

Vladislav Vladimirovich Yemelyanov

St. Petersburg State University

Email: bootika@mail.ru
Dept. Of Genetics and Biotechnology

Lyudmila Alekseevna Lutova

St. Petersburg State University

Email: la.lutova@gmail.com
Dept. Of Genetics and Biotechnology

References

  1. Бояринцев Л. Е. (2003) Разработка и применение препаратов интерферона и биологически активных добавок в ветеренарии. Дисс. на соиск. уч. ст. докт. ветер, наук. Воронеж.
  2. Глеба Ю. Ю. (1998) Биотехнология растений. Соросовский образовательный журнал. № 6: С. 3-8.
  3. Градобоева А. Е., Падкина М. В. (2008) Изучение влияния продукции гетерологичного белка на физиологическое состояние дрожжей Saccharomyces cerevisiae и Pichia pastoris. Вестник СПбГУ. Сер. 3. № 2: С. 56-61.
  4. Грант В. (1989) Эволюционный процесс. Москва: Мир.
  5. Дейнеко Е. В. (2012) Генетически модифицированные растения - продуценты белков медицинского назначения. Вестник Томского государственного университета. Биология. № 2. (18): С. 41-51.
  6. Ершов В. И. (2008) Наглядная гематология./Ред. Ершов В. И.//Москва: ГЭОТАР-Меди.
  7. Катохин А. В., Кузнецова Т. Н., Омельянчук Н. А. (2006) миРНК - новые регуляторы активности генов у эукариот. Вестник ВОГиС. Т. 10: С. 241-272.
  8. Кетлинский С. А., Симбирцев А. С., Воробьев А. А. (1992) Эндогенные иммуномодуляторы СПб.: Гиппократ.
  9. Лутова Л. А. (2010) Биотехнология высших растений. 2-е изд. СПб.: Изд-во Санкт-Петербургского государственного университета.
  10. Мирошников П. Н., Лебедев Л. Р., Терещенко Т. А. с соавт. (2003) Разработка способов получения интерферона-гамма и его мутантного аналога дельтаферона. Биотехнология: состояние и перспективы развития. Т. 152: С. 78-82.
  11. Падкина М. В., Парфёнова Л. В., Градобоева А. Е., СамбукЕ. В. (2010) Синтез гетерологичных интерферонов в клетках дрожжей Pichia pastoris. Прикл. Биохим. Микробиол. Т. 46: С. 448-455.
  12. Придыбайло Н. Д. (1991) Иммунодефициты у сельскохозяйственных животных и птиц. Профилактика и лечение их иммуностимуляторами. Москва: ВАСХНИЛ.
  13. Рукавцова Е. Б., Бурьянов Я. И., Шульга Н. Я., Быков В. А. (2006) Трансгенные растения для фармакологии. Вопросы биологической, медицинской и фармацевтической химии. № 2: С. 3-12.
  14. Савельева Н. В., Курдюков И. Д., Дудник Е. Э. с соавт. (2009) Растения-продуценты бычьего гамма-интерферона для профилактики туберкулеза и лейкемии крупного рогатого скота. Вестник С.-Петербургского ун-та. Сер. 3. №. 4: С. 65-80.
  15. Савельева Н. В., Лутова Л. А. (2010) Растения - продуценты рекомбинантных белков медицинского назначения. Продуценты γ-интерферонабыка. Саарбрюкен: Изд-во LAPLAMBERT Academic Publishing.
  16. Симбирцев А. С. (2013)Достижения и перспективы использования рекомбинантных цитокинов в клинической практике. Медицинский академический журнал. Т. 13: С. 7-22.
  17. Федоров Ю. Н., Верховский О. А. (1996) Иммунодефициты домашних животных Москва: Москва.
  18. Цыганков М. А., Зобнина А. Е., Падкина М. В. (2014) Синтез модифицированных, устойчивых к протеолитической деградации интерферонов-гамма в дрожжах Pichia pastoris. Прикл. Биохим. Микробиол. Т. 50: С. 429-436.
  19. Шульга Н. Я., Рукавцова Е. Б., Крымский М. А. с соавт. (2004) Экспрессия поверхностного антигена вируса гепатита В в трансгенных растениях картофеля и его характеристика. Биохимия. T. 69: C. 1422-1430.
  20. Arango J., Salazar B., Welsch R. et al. (2010) Putative storage root specific promoters from cassava and yam: cloning and evaluation in transgenic carrots as a model system. Plant Cell Rep. V. 29: P. 651-659.
  21. Arlen P. A., Falconer R., Cherukumilli S. etal. (2007)Field production and functional evaluation of chloroplast-derived interferon-α2b. Plant Biotechnol. J. V. 5: P. 511-525.
  22. Assenberg R., Wan P., Geisse S., Mayr L. (2013) Advances in recombinant protein expression for use in pharmaceutical research. Curr. Opin. Struct. Biol. V. 23: P. 393-402.
  23. Barta A., Sommergruber K., Thompson D. et al. (1986) The expression of a nopalin synthase human growth hormone chimaeric gene in transformed tobacco and sunflower callus tissue. Plant Mol. Biol. V. 6: P. 347-357.
  24. Barton K. A., Binns A. N., Matzke A. J., Chilton M. D. (1983) Regeneration of intact tobacco plants containing full length copies of genetically engineering T-DNA, and transmission of T-DNA to R1 progeny. Cell. V. 32: P. 1033-1043.
  25. Basaran P., Rodriguez-Cerezo E. (2008) Plnt molecular farming: opportunities and challenges. Crit. Rev. Biotechnol. V. 28: P. 153-172.
  26. Bosze Z., Baranyi M., Whitelaw C. (2008) Producing recombinant human milk proteins in the milk of livestock species. Adv. Exp. Med. Biol. V. 606: P. 357-393.
  27. Bucherna N., Okkels F. T., Palmgren C. (2004) Developmental timing of transgene expression in Arabidopsis thaliana using gene silencing mutants and matrix attachment regions. Plant J. V. 39: P. 440-449.
  28. Chen T. L., Lin Y. L., Lee Y. L. et al. (2004) Expression of bioactive human interferon-gamma in transgenic rice cell suspension cultures. Transgenic Res. V. 13: P. 499-510.
  29. Chikwamba R., Cunnick J., Hathaway D. et al. (2002) A functional antigen in a practical crop: LT-B producing maize protects mice against Escherichia coli heat labile enterotoxin (LT) and cholera toxin (CT). Transgenic Res. V. 11: P. 497-493.
  30. Chong D. K. X., Roberts W., Arakawa T. et al. (1997) Expression of the human milk protein β-casein in transgenic potato plants. Transgenic Res. V. 6: P. 289-296.
  31. Clausen R. E. (1941) Polyploidy in Nicotiana. Amer. Nat. J. N 75: P. 291-306.
  32. Cramer C. L., Weissenborn D. L., Oishi K. K. et al. (1996) Bioproduction of human enzymes in transgenic tobacco. Ann. NY Acad. Sci. V. 792: P. 62-71.
  33. Da Cunha N. B., Vianna G. R., Da Almeida L. T., Rech E. (2014) Molecular farming of human cytokines and blood products from plants: Challenges in biosynthesis and detection of plant-produced recombinant proteins. Biotechnol. J. V. 9: P. 39-50.
  34. Daniel K., Chong X., Langridge W. H. R. et al. (2000) Expression of full-length bioactive antimicrobial human lactoferrin in potato plants. Transgenic Res. V. 9: P. 71-78.
  35. Daniell H., Ruiz G., Denes B. et al. (2009) Optimization of codon composition and regulatory elements for expression of human insulin like growth factor-1 in transgenic chloroplasts and evaluation of structural identity and function. BMC Biotechnol. V. 9: Art. 33.
  36. De Jaeger G., De Wilde C., Eeckhout D. et al. (2000) The plantibody approach: expression of antibody genes in plants to modulate plant metabolism or to obtain pathogen resistance. Plant Mol. Biol. V. 43: P. 419-428.
  37. Delores S. C., Gardner R. C. (1988) Expression and inheritance of kanamicin resistance in number of transgenic petunias ganerated by Agrabacterium-mediated transformation. PlantMol. Biol. V. 11: P. 355-364.
  38. Desai P., Shrivastava N., Padh H. (2010) Production of heterologous proteins in plants: strategies for optimal expression. Biotechnol. Adv. V. 28: P. 427-435.
  39. Desai U. A., Sur G., Daunert S. et al. (2002) Expression and affinity purification of recombinant proteins from plants. Protein Expr. Purif. V. 25: P. 195-202.
  40. Dieryck W., Pagnier J., Poyart C. et al. (1997) Human haemoglobin from transgenic tobacco. Nature. V. 386: P. 29-30.
  41. Edelbaum O., Stein D., Holland N. et al. (1992)Expression of active human interferon-beta in transgenic plants. J. Interferon Res. V. 12: P. 449-453.
  42. Flynn J. L., Chan J., Triebold K. J. et al. (1993)An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. V. 178: P. 2249-2253.
  43. Forsbach A., Schubert D., Lechtenberg B. et al. (2003) Comprehensive characterization of single copy T-DNA insertions in the Arabidopsis thaliana genome. Plant Mol. Biol. V. 52: P. 161-176.
  44. Fukuzawa N., Tabayashi N., Okinaka Y. et al. (2010) Production of biologically active Atlantic salmon interferon in transgenic potato and rice plants. J. Biosci. Bioeng. V. 110: P. 201-207.
  45. Furner I. J., Sheikh M. A., Collett C. E. (1998) Gene silencing and homology-dependent gene silencing in Arabidopsis: genetic modifiers and DNA methylation. Genet. V. 149: P. 651-662.
  46. Gao C., Nielsen K. (2013) Comparison between Agrobacterium-mediated and direct gene transfer using the gene gun. Meth. Mol. Biol. V. 940: P.3-16.
  47. Gleba Y., Tuse D., Giritch A. (2014) Plant viral vectors for delivery by Agrobacterium. Curr. Top. Microbiol. Immunol. V. 375: P. 155-192.
  48. Hellwig S., Drossard J., Twyman R. M., Fischer R. (2004) Plant cell cultures for the production of recombinant proteins. Nature Biotechnol. V. 22: P. 1415-1422.
  49. Herrera-Estrella L., Depicker A., van Montagu M., Schell J. (1983) Expression of chimeric genes transferred into plant cells using a Ti-plasmid-derived vector. Nature. V. 303: P. 209-213.
  50. Hiatt A., Cafferkey R., Bowdish K. (1989) Production of antibodies in transgenic plant. Nature. V. 342: P. 76-78.
  51. 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. Biotech. Biochem. V. 57: P. 1477-1481.
  52. Hood E., Witcher D., Maddock S. et al. (1997) Commercial production of avidin from transgenic maize: characterization of transformant, production, processing, extraction and purification. Mol. Breed. V. 3: P. 291-306.
  53. Horsh R. B., Fraley R. T., Rogers S. G. et al. (1984) Inheritance of functional foreign genes in plants. Science. V. 223: P. 496-498.
  54. Iglesias V. A., Moscone E. A., Papp I. et al. (1997) Molecular and cytogenetic analusis of stably and unstably expressed transgene loci in tobacco. Plant Cell. V. 9: P. 1251-1264.
  55. Key S., Ma J. K. C., Drake P. M. W. (2008) Genetically modified plants and human helth. J. R. Soc. Me. V. 101: P. 290-298.
  56. Kim T.-G., Yang M.-S. (2010) Current trends in edible vaccine development using transgenic plants. Biotechnol. Bioprocess Eng. V. 15. P. 61-65.
  57. Kong Q., Richter L., Yang Y. F. et al. (2001) Oral immunization with hepatitis B surface antigen expressed in transgenic plants. Proc. Natl. Acad. Sci. USA. V. 98: P. 11 539-11 544.
  58. Koprivova A., Stemmer C., Altmann F. et al. (2004) Targeted knockouts of Physcomitrella lacking plant-specific immunogenic N-glycans. Plant Biotechnol. J. V. 2: P. 517-523.
  59. Lambertz C., Garvey M., Klinger J. et al. (2014) Challenges and advances in the heterologous expression of cellulolytic enzymes: a review. Biotechnol. Biofuels. V. 7: Art. 135.
  60. Lamphear B. J., Jilka J. M., Kesl L. et al. (2004) A corn-based delivery system for animal vaccines: an oral transmissible gastroenteritis virus vaccine boosts lactogenic immunity in swine. Vaccine. V. 22: P. 2420-2424.
  61. Larrick J. W., Yu L., Naftzger C. et al. (2001) Production of secretory IgA antibodies in plants. Biomol. Eng. V. 18: P. 87-94.
  62. Linn F., Heidmann I., Saedler H., Meyer P. (1990) Epigenetic changes in the expression of the maize Al gene in Petunia hybrida: role of numbers of integrated copies and state of methylation. Mol. Gen. Genet. V. 222: P. 329-336.
  63. Luchakivskaya Yu., Kishchenko O., Gerasymenko I. et al. (2011) High-level expression of human interferon alpha-2b in transgenic carrot (Daucus carota L.) plants. Plant Cell Rep. V. 30: P. 407-415.
  64. Ma J. K., Drake P. M., Christou P. (2003) The production of recombinant pharmaceutical proteins in plants. Nat. Rev. Genet. V.4: P. 794-805.
  65. Mason H. S., Lam D. M., Arntzen C. J. (1992) Expression of hepatitis B surface antigen in transgenicplants. Proc. Natl. Acad. Sci. USA. V. 89: P. 11 745-11 749.
  66. Matsumoto S., Ikura K., Ueda M., Sasaki R. (1995) Characterization of a human glycoprotein (erythropoietin) produced in cultured tobacco cells. Plant Mol. Biol. V. 27: P. 1163-1172.
  67. McCormick A. A., Kumagai M. H., Hanley K. 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. V. 96: P. 703-708.
  68. Merle C., Perret S., Lacour T. et al. (2002) Hydroxylated human homotrimeric collagen I in Agrobacterium tumefaciens-mediated transient expression and in transgenic tobacco plant. FEBS Lett. V. 515: P. 114-118.
  69. Meyer P., Linn F., Heidmann I. et al. (1992) Endogenous and environmental factors influence 35S promoter methylation of a maize Al gene construct in transgenic petunia and its colour phenotype. Mol. Gen. Genet. V. 231: P. 345-352.
  70. Mittelsten S. O., Paszkowsky J., Potrykus I. (1991) Reverseble inactivation of a transgene in Arabidopsis thaliana. Mol. Gen. Genet. V. 228: P. 104-112.
  71. Morino K., Olsen O. A., Shimamoto K. (1999) Silencing of an aleurone-specific gene in transgenic rice is caused by a rearranged transgene. Plant J. V. 17: P. 275-285.
  72. Noh S. A., Lee H. S., Huh G. H. etal. (2012) A sweetpotato SRD1 promoter confers strong root-, taproot-, and tuber-specific expression in Arabidopsis, carrot, and potato. Transgenic Res. V. 21: P. 265-278.
  73. Nykiforuk C. L., Boothe J. G., Murray E. W. et al. (2006) Transgenic expression and recovery of biologically active recombinant human insulin from Arabidopsis thaliana seeds. Plant Biotechnol. J. V. 4: P. 77-85.
  74. ObembeO. O., Popoola J. O., Leelavathti S., Reddy S. V. (2011) Advances in plant molecular farming. Biotechnol. Adv. V. 29: P. 210-222.
  75. Oksman-Caldentey K.-M., Inze D. (2004) Plant cell factories in the post-genomic era: new ways to produce designer secondary metabolites. Trends Plant Sci. V. 9: P. 433-440.
  76. Parmenter D. L., Boothe J. G., van Rooijen G. J. H. et al. (1995) Production of biologically active hirudin in plant seeds using oleosin partitioning. Plant Mol. Biol. V. 29: P. 1167-1180.
  77. Pestka S., Langer J. A., Zoon K. C., Samuel C. E. (1987) Interferons and their actions. Ann. Rev. Biochem. V. 56: P. 727-777.
  78. Potula H. H. S. K., Kathuria S. R., Ghosh A. K. et al. (2008) Transient expression, purification and characterization of bioactive human fibroblast growth factor 8b in tobacco plants. Transgenic Res. V. 17: P. 19-32.
  79. Rance I., Norre F., Gruber V., Theisen M. (2002) Combination of viral promoter sequences to generate highly active promoters for heterologous therapeutic protein over-expression in plants. Plant Sci. V. 162: P. 833-842.
  80. Richter L. J., Thanavala Y., Arntzen C. J., Mason H. S. (2000) Production of hepatitis B surface antigen in transgenic plants for oral immunization. Nat. Biotechnol. V. 18: P. 1167-1171.
  81. Ruggiero F., Exposito J. Y., Bournat P. et al. (2000) Triple helix assebly and processing of human collagen produced in transgenic tobacco plants. FEBS Lett. V. 469: P. 132-136.
  82. Sallaud C., Meynard D., van Boxtel J. et al. (2003)Highly efficient production and characterization of T-DNA plants for rice (Oryza sativa L.) functional genomics. Theor. Appl. Genet. V. 106: P. 1396-1408.
  83. Scheller J., Henggeler D., Viviani A., Conrad U. (2004) Purification of spider silk-elastin from transgenic plants and application for human chondrocyte proliferation. Transgenic Res. V. 13: P. 51-57.
  84. Schmulling Т., Schell, J. (1993) Transgenic tobacco plants regenerated from leaf disks can be periclinal chimeras. Plant Mol. Biol. V. 21: P. 705-708.
  85. Schroder K., Hertzog P. J., Ravasi T., Hume D. A. (2004)Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol. V. 75: P. 163-189.
  86. Shaaltiel Y., Bartfeld D., Hashmueli S. et al. (2007) Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher’s disease using plant cell system. Plant Biotechnol. J. V. 5: P. 579-590.
  87. Sharma A. K., Sharma M. K. (2009) Plants as bioreactors: Recent developments and emerging opportunities. Biotechnology Advances. V. 27: P. 811-832.
  88. Sijmons P. C., Dekker B. M., Schrammeijer B. et al. (1990) Production of correctly processed human serum albumin in transgenic plants. Biotechnol. (NY). V. 8: P. 217-221.
  89. Sirko A., Vanek T., Gora-Sochacka A., Redkiewicz P. (2011) Recombinant cytokines from plants. Int. J. Mol. Sci. V. 12: P. 3536-3552.
  90. Smith M. L., Mason H. S., Shuler M. L. (2002) Hepatitis B surface antigen (HBsAg) expression in plant cell culture: Kinetics of antigen accumulation in batch culture and its intracellular form. Biotechnol. Bioeng. V. 80: P. 812-822.
  91. Stam M., Viterbo A., Mol J. N. M., Kooter J. M. (1998) Position-dependent methylation and transcriptional silencing of transgenes in inverted T-DNA repeats: implications for posttranscriptional silencing of homologous host genes in plant. Mol. Cell. Biol. V. 18: P. 6165-6177.
  92. Staniek A., Bouwmeester H., Fraser P. D. et al. (2013) Natural products - modifying metabolite pathways in plants. Biotechnol. J. V. 8: P. 1159-1171.
  93. Stiles A., Liu C. (2013) Hairy root culture: bioreactor design and process intensification. Adv. Biochem. Engineer. Biotechnol. V. 134: P. 91-114.
  94. Stoger E., Vaquero C., Torres E. et al. (2000) Cereal crops as viable production and storage systems for pharmaceutical scFv antibodies. Plant Mol Biol. V. 42: P. 583-590.
  95. Tacket C. O., Mason H. S., Losonsky G. et al. (1998) Immunogenicity in humans of a recombinant bacterial antigen delivered in a transgenic potato. Nat. Med. V. 4: P. 607-609.
  96. Tacket C. O., Mason H. S., Losonsky G. et al. (2000) Human immune responses to a novel norwalk virus vaccine delivered in transgenic potatoes. J. Infect. Dis. V. 182: P. 302-305.
  97. Terashima M., Murai Y., Kawamura M. et al. (1999) Production of functional human α1-antitrypsin by plant cell culture. Appl. Microbiol. Biotechnol. V. 52: P. 516-523.
  98. Thanavala Y., Mahoney M., Pal S. et al. (2005) Immunogenicity in humans of an edible vaccine for hepatitis B. Ibid. V. 102: P. 3378-3382.
  99. Thanavala Y., Yang Y. F., Lyons P. et al. (1995) Immunogenicity of transgenic plant-derived hepatitis B surface antigen. Proc. Natl. Acad. Sci. USA. V. 92: P. 3358-3361.
  100. Thomas B. R., Deynze A. V., Bradford K. J. (2002) Production of therapeutic proteins in plants. Agricultural biothechnology in California series. 342 p.
  101. Trexler M. M., McDonald K. A., Jackman A. P. (2002) Bioreactor production of human 1-antitrypsin using metabolically regulated plant cell cultures. Biotechnol. Prog. V. 18: P. 501-508.
  102. Trimble R. B., Atkinson P. H., Tschopp R. R., Maley F. (1991) Structure of oligosaccharides on Saccharomyces SUC2 invertase secreted by the methylotrophic yeast Pichia pastoris. J. Biol. Chem. V. 266: P. 22 807-22 817.
  103. Vandekerckhove J., Van Damme J., Van Lijsebettens M. et al. (1989) Enkephalins produced in transgenic plants using modified 2S seed storage proteins. BioTechnology. V. 7: P. 929-932.
  104. Veluthambi K., Jayaswal R. K., Gelvin S. B. (1987) Virulence genes A, G, and D mediate the double-stranded border cleavage of T-DNA from the Agrobacterium Ti plasmid. Proc. Natl. Acad. Sci. USA. V. 84: P. 1881-1885.
  105. Vesosky В., Turner O. C., Turner J., Orme I. M. (2004) Gamma interferon production by bovine gamma delta T cells following stimulation with mycobacterial mycolylarabinogalactan peptidoglycan. Infection and immunity. V. 72: P. 4612-4618.
  106. Weise A., Altmann F., Rodriguez-Franco M. et al. (2007)High-level expression of secreted complex glycosylated recombinant human erythropoietin in the PhyscomitrellaΔ-fuc-t Δ-xyl-t mutant. Plant Biotechnol. J. V. 5: P. 389-401.
  107. Woodard S. L., Mayor J. M., Bailey M. R. et al. (2003) Maize (Zea mays)-derived bovine trypsin: characterization of the first large-scale, commercial protein product from transgenic plants. Biotechnol. Appl. Biochem. V. 38: P. 123-130.
  108. Yang D. C., Guo F. L., Liu B. et al. (2003) Expression and localization of human lysozyme in the endosperm of transgenic rice. Planta. V. 216: P. 597-603.
  109. Yu J., Langridge W. H. (2001) A plant-based multicomponent vaccine protects mice from enteric diseases. Nat. Biotechnol. V. 19: P. 548-552.
  110. Zeitlin L., Olmsted S. S., Moench T. R. et al. (1998) A humanized monoclonal antibody produced in transgenic plants for immunoprotection of the vagina against genital herpes. Nat. Biotechnol. V. 16: P. 1361-1364.
  111. Zhong G.-Y., Peterson D., Delaney D. E. et al. (1999) Commercial production of aprotinin in transgenic maize seeds. Mol. Breed. V. 36: P. 345-356.

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