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<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">vavilov</journal-id><journal-title-group><journal-title xml:lang="ru">Вавиловский журнал генетики и селекции</journal-title><trans-title-group xml:lang="en"><trans-title>Vavilov Journal of Genetics and Breeding</trans-title></trans-title-group></journal-title-group><issn pub-type="epub">2500-3259</issn><publisher><publisher-name>Institute of Cytology and Genetics of Siberian Branch of the RAS</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.18699/VJ17.322</article-id><article-id custom-type="elpub" pub-id-type="custom">vavilov-1277</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>АКТУАЛЬНЫЕ ТЕХНОЛОГИИ ГЕНЕТИКИ И КЛЕТОЧНОЙ БИОЛОГИИ</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>MAINSTREAM TECHNOLOGIES IN GENETICS AND CELL BIOLOGY</subject></subj-group></article-categories><title-group><article-title>Растительные системы экспрессии  в качестве продуцентов рекомбинантных фармацевтически ценных белков</article-title><trans-title-group xml:lang="en"><trans-title>Plant expression systems  for production of recombinant pharmaceutically important proteins</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Дейнеко</surname><given-names>Е. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Deineko</surname><given-names>E. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Новосибирск.</p></bio><bio xml:lang="en"><p>Novosibirsk.</p></bio><email xlink:type="simple">deineko@bionet.nsc.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Загорская</surname><given-names>А. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Zagorskaya</surname><given-names>A. A.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Новосибирск.</p></bio><bio xml:lang="en"><p>Novosibirsk.</p></bio><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru">Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук.<country>Россия</country></aff><aff xml:lang="en">Institute of Cytology and Genetics SB RAS.<country>Russian Federation</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2017</year></pub-date><pub-date pub-type="epub"><day>21</day><month>01</month><year>2018</year></pub-date><volume>21</volume><issue>8</issue><fpage>979</fpage><lpage>985</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Дейнеко Е.В., Загорская А.А., 2018</copyright-statement><copyright-year>2018</copyright-year><copyright-holder xml:lang="ru">Дейнеко Е.В., Загорская А.А.</copyright-holder><copyright-holder xml:lang="en">Deineko E.V., Zagorskaya A.A.</copyright-holder><license license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://vavilov.elpub.ru/jour/article/view/1277">https://vavilov.elpub.ru/jour/article/view/1277</self-uri><abstract><p>Рынок фармацевтически ценных белков – наиболее быстро развивающийся сегмент экономики. Большая часть биофармацевтиков получена в клетках млекопитающих и микроорганизмов, однако обе системы обладают рядом недостатков. Растительные клетки сочетают в себе достоинства эукариотической системы наработки белка и простоту и дешевизну бактериальной. Использование растений для получения рекомбинантных белков – экономически значимое и перспективное направление. Преимуществом растительных систем является более низкая стоимость культивирования клеток. Они свободны от нежелательных компонентов, таких как эндотоксины бактерий, гипергликозилированные белки, продуцируемые дрожжами, патогены животных и человека в клеточных культурах трансгенных животных. Растения относятся к высшим эукариотам, поэтому в их клетках происходит полноценный фолдинг и образование сложных мультимерных белковых комплексов, а также значительная часть посттрансляционных модификаций аналогично таковым в клетках млекопитающих. Развиваемые ныне растительные системы экспрессии рекомбинантных белков чрезвычайно разнообразны и насчитывают более 100 различных технологий, основанных на разных видах растений, способах переноса генов, экспрессионных стратегиях, методах последующего извлечения целевого белка и пр. К ним относятся ядерная и пластидная трансформация, транзиентная и стабильная экспрессия при трансформации с помощью агробактериального переноса, бомбардировки или электропорации, культивирование целых наземных или водных растений, растительных тканей или суспензионных клеточных культур в качестве экспрессионных систем. В обзоре анализируется современное состояние исследований в области использования растительных систем экспрессии для наработки рекомбинантных фармацевтических белков. Сделан акцент на преимуществах культур растительных клеток по сравнению с другими системами экспрессии. Описаны растительные системы для наработки рекомбинантных белков, такие как транспластомные растения, культуры мхов и водных растений, а также суспензионные культуры клеток высших растений. Рассмотрено современное состояние рынка рекомбинантных белков, полученных с применением растительных систем экспрессии. Обсуждаются перспективы растительных («съедобных») вакцин, созданных на основе генетически модифицированных растений.</p></abstract><trans-abstract xml:lang="en"><p>The market of pharmaceutically valuable proteins is the fastest growing segment of the economy. Most biopharmaceuticals have been obtained in mammalian and microorganism cells, but both systems have a number of disadvantages. Plant cells combine the advantages of the eukaryotic system of protein production and the simplicity and cheapness of the bacterial, and the use of plants for the production of recombinant proteins is an economically important and promising direction. The advantage of plant systems is the lower cost of cell cultivation. They are free from unwanted components, such as bacterial endotoxins, hyperglycosylated proteins produced by yeast, animal and human pathogens in cell cultures of transgenic animals. In addition, plants are higher eukaryotes, and therefore fullvalue folding and the formation of multimeric protein complexes occur in their cells, as well as a significant portion of post­translational modifications similar to those in mammalian cells. The currently developed plant expression systems for recombinant proteins are extremely diverse and number more than 100 different technologies based on different plant species, gene transfer methods, expression strategies, methods for the subsequent extraction of the target protein, etc. This is nuclear and plastid transformation, transient and stable expression during transformation using agrobacterial transport, bombardment or electroporation, cultivation of whole terrestrial or aquatic plants, plant tissues or suspension cell cultures as expression systems. The review examines the current state of research in the use of plant expression systems for the production of recombinant proteins for pharmaceuticals. The emphasis was placed on the advantages of plant cell cultures in comparison with other expression systems. Specific examples discuss promising plant systems for the production of recombinant proteins, such as transplastomic plants, moss and aquatic plant cultures, as well as suspension cultures of cells of higher plants. The current state of the market for recombinant proteins obtained using plant expression systems is considered. The prospects of creating plant (“edible”) vaccines based on genetically modified plants are discussed.</p></trans-abstract><kwd-group xml:lang="ru"><kwd>системы экспрессии</kwd><kwd>трансгенные растения</kwd><kwd>биопродуценты</kwd><kwd>рекомбинантные белки</kwd><kwd>растительные вакцины</kwd></kwd-group><kwd-group xml:lang="en"><kwd>expression systems</kwd><kwd>transgenic plants</kwd><kwd>bioproducers</kwd><kwd>recombinant proteins</kwd><kwd>plant vaccines</kwd></kwd-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">Almaraz-Delgado A.L., Flores-Uribe J., Perez-Espana V.H., SalgadoManjarrez E., Badillo-Corona J.A. Production of therapeutic proteins in the chloroplast of Chlamydomonas reinhardtii. AMB Express. 2014;4:57. DOI 10.1186/s13568-014-0057-4. PMID:25136510.</mixed-citation><mixed-citation xml:lang="en">Almaraz-Delgado A.L., Flores-Uribe J., Perez-Espana V.H., SalgadoManjarrez E., Badillo-Corona J.A. Production of therapeutic proteins in the chloroplast of Chlamydomonas reinhardtii. AMB Express. 2014;4:57. DOI 10.1186/s13568-014-0057-4. PMID:25136510.</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">Apeler H., Peters J., Schroder W. Expression, purification, and pharmacological characterization of a recombinant aprotinin variant. Drug Res. 2004;54(8):483-497. DOI 10.1055/s-0031-1297003.</mixed-citation><mixed-citation xml:lang="en">Apeler H., Peters J., Schroder W. Expression, purification, and pharmacological characterization of a recombinant aprotinin variant. Drug Res. 2004;54(8):483-497. DOI 10.1055/s-0031-1297003.</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">Arakawa T., Chong D.K.X., Langridge H.R. Efficacy of food plantbased oral cholera toxin B sununit vaccine. Nat. Biotechnol. 1998; 16:292-297. DOI 10.1038/nbt0398-292.</mixed-citation><mixed-citation xml:lang="en">Arakawa T., Chong D.K.X., Langridge H.R. Efficacy of food plantbased oral cholera toxin B sununit vaccine. Nat. Biotechnol. 1998; 16:292-297. DOI 10.1038/nbt0398-292.</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">Boynton J.E., Gilham N.W., Harris S.E. Chloroplast transformation in Chlamydomonas with high velocity microprojectiles. Science. 1988; 240:1534-1538. DOI 10.1126/science.2897716.</mixed-citation><mixed-citation xml:lang="en">Boynton J.E., Gilham N.W., Harris S.E. Chloroplast transformation in Chlamydomonas with high velocity microprojectiles. Science. 1988; 240:1534-1538. DOI 10.1126/science.2897716.</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Casteleijn M., Richardson D. Engineering cells and proteins – creating pharmaceuticals. Eur. Pharm. Rev. 2014;19(4):12-19.</mixed-citation><mixed-citation xml:lang="en">Casteleijn M., Richardson D. Engineering cells and proteins – creating pharmaceuticals. Eur. Pharm. Rev. 2014;19(4):12-19.</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Cox K.M., Sterling J.D., Regan J.T. Glycan optimization of a human monoclonal antibody in the aquatic plant Lemna minor. Nat. Biotechnol. 2006;24:1591-1597. DOI 10.1038/nbt1260.</mixed-citation><mixed-citation xml:lang="en">Cox K.M., Sterling J.D., Regan J.T. Glycan optimization of a human monoclonal antibody in the aquatic plant Lemna minor. Nat. Biotechnol. 2006;24:1591-1597. DOI 10.1038/nbt1260.</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">Daniell H. Transgenic containment by maternal inheritance: effective or elusive. Proc. Natl. Acad. Sci. USA. 2007;1104:6879-6880. DOI 10.1073/pnas.0702219104.</mixed-citation><mixed-citation xml:lang="en">Daniell H. Transgenic containment by maternal inheritance: effective or elusive. Proc. Natl. Acad. Sci. USA. 2007;1104:6879-6880. DOI 10.1073/pnas.0702219104.</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Daniell H., Chebolu S., Kumar S., Singleton M., Falconer R. Chloroplast-derived vaccine antigens and other therapeutic proteins. Vaccine. 2005;23:1779-1783. DOI 10.1016/j.vaccine.2004.11.004.</mixed-citation><mixed-citation xml:lang="en">Daniell H., Chebolu S., Kumar S., Singleton M., Falconer R. Chloroplast-derived vaccine antigens and other therapeutic proteins. Vaccine. 2005;23:1779-1783. DOI 10.1016/j.vaccine.2004.11.004.</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">DeCosa B., Moar W., Lee S.B., Miller M., Daniell H. Overexpression of the Bt cry2Aa2 operon in chloroplasts leads to formation of insecticidal crystals. Nat. Biotechnol. 2001;19:71-74. DOI 10.1038/83559.</mixed-citation><mixed-citation xml:lang="en">DeCosa B., Moar W., Lee S.B., Miller M., Daniell H. Overexpression of the Bt cry2Aa2 operon in chloroplasts leads to formation of insecticidal crystals. Nat. Biotechnol. 2001;19:71-74. DOI 10.1038/83559.</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">Desai P.N., Shrivastava N., Padh H. Production of heterologous proteins in plants: Strategies for optimal expression. Biotechnol. Adv. 2010;28:427-435. DOI 10.1016/j.biotechadv.2010.01.005.</mixed-citation><mixed-citation xml:lang="en">Desai P.N., Shrivastava N., Padh H. Production of heterologous proteins in plants: Strategies for optimal expression. Biotechnol. Adv. 2010;28:427-435. DOI 10.1016/j.biotechadv.2010.01.005.</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">Dufourmantel N., Pelissier B., Garçon F., Peltier G., Ferullo J.M., Tissot G. Generation of fertile transplastomic soybean. Plant Mol. Biol. 2004;55:479-489. DOI 10.1007/s11103-004-0192-4.</mixed-citation><mixed-citation xml:lang="en">Dufourmantel N., Pelissier B., Garçon F., Peltier G., Ferullo J.M., Tissot G. Generation of fertile transplastomic soybean. Plant Mol. Biol. 2004;55:479-489. DOI 10.1007/s11103-004-0192-4.</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">Fischer R., Schillberg S., Hellwig S., Twyman R.M., Drossard J. GMP issues for recombinant plant-derived pharmaceutical proteins. Biotechnol. Adv. 2012;30:434-439. DOI 10.1016/j.biotechadv.2011.08.007.</mixed-citation><mixed-citation xml:lang="en">Fischer R., Schillberg S., Hellwig S., Twyman R.M., Drossard J. GMP issues for recombinant plant-derived pharmaceutical proteins. Biotechnol. Adv. 2012;30:434-439. DOI 10.1016/j.biotechadv.2011.08.007.</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">Franklin S.E., Mayfield S.P. Prospects for molecular farming in the green algae Chlamydomonas. Curr. Opin. Plant Biol. 2004;7:159165. DOI 10.1016/j.pbi.2004.01.012.</mixed-citation><mixed-citation xml:lang="en">Franklin S.E., Mayfield S.P. Prospects for molecular farming in the green algae Chlamydomonas. Curr. Opin. Plant Biol. 2004;7:159165. DOI 10.1016/j.pbi.2004.01.012.</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">Gelvin S.B. Agrobacterium-mediated plant transformation: the biology behind the “gene-jockeying” tool. Microbiol. Mol. Biol. Rev. 2003;67(1):16-37. DOI 10.1128/MMBR.67.1.16-37.2003.</mixed-citation><mixed-citation xml:lang="en">Gelvin S.B. Agrobacterium-mediated plant transformation: the biology behind the “gene-jockeying” tool. Microbiol. Mol. Biol. Rev. 2003;67(1):16-37. DOI 10.1128/MMBR.67.1.16-37.2003.</mixed-citation></citation-alternatives></ref><ref id="cit15"><label>15</label><citation-alternatives><mixed-citation xml:lang="ru">Gleba Y., Klimyuk V., Marillonnet S. Magnifection – a new platform for expressing recombinant vaccines in plants. Vaccine. 2005;23:2042-2048. DOI 10.1016/j.vaccine.2005.01.006.</mixed-citation><mixed-citation xml:lang="en">Gleba Y., Klimyuk V., Marillonnet S. Magnifection – a new platform for expressing recombinant vaccines in plants. Vaccine. 2005;23:2042-2048. DOI 10.1016/j.vaccine.2005.01.006.</mixed-citation></citation-alternatives></ref><ref id="cit16"><label>16</label><citation-alternatives><mixed-citation xml:lang="ru">Gleba Y., Klimyuk V., Marillonnet S. Viral vectors for the expression of proteins in plants. Curr. Opin. Biotechnol. 2007;18:134-141. DOI 10.1016/j.copbio.2007.03.002.</mixed-citation><mixed-citation xml:lang="en">Gleba Y., Klimyuk V., Marillonnet S. Viral vectors for the expression of proteins in plants. Curr. Opin. Biotechnol. 2007;18:134-141. DOI 10.1016/j.copbio.2007.03.002.</mixed-citation></citation-alternatives></ref><ref id="cit17"><label>17</label><citation-alternatives><mixed-citation xml:lang="ru">Haq T.A., Mason H.S., Clements J.D., Arntzen C.J. Oral immunization with a recombinant bacterial antigen produced in transgenic plants. Science. 1995;268:714-719. DOI 10.1126/science.7732379.</mixed-citation><mixed-citation xml:lang="en">Haq T.A., Mason H.S., Clements J.D., Arntzen C.J. Oral immunization with a recombinant bacterial antigen produced in transgenic plants. Science. 1995;268:714-719. DOI 10.1126/science.7732379.</mixed-citation></citation-alternatives></ref><ref id="cit18"><label>18</label><citation-alternatives><mixed-citation xml:lang="ru">Hellwig S., Drossard J., Twyman R.M., Fischer R. Plant cell cultures for the production of recombinant proteins. Nat. Biotechnol. 2004; 22:1415-1422. DOI 10.1016/j.biotechadv.2011.08.007.</mixed-citation><mixed-citation xml:lang="en">Hellwig S., Drossard J., Twyman R.M., Fischer R. Plant cell cultures for the production of recombinant proteins. Nat. Biotechnol. 2004; 22:1415-1422. DOI 10.1016/j.biotechadv.2011.08.007.</mixed-citation></citation-alternatives></ref><ref id="cit19"><label>19</label><citation-alternatives><mixed-citation xml:lang="ru">Howard J.A. Commercialization of biopharmaceutical and bioindustrial proteins from plants. Crop Sci. 2005;45:468-472. DOI 10.2135/cropsci2005.0468.</mixed-citation><mixed-citation xml:lang="en">Howard J.A. Commercialization of biopharmaceutical and bioindustrial proteins from plants. Crop Sci. 2005;45:468-472. DOI 10.2135/cropsci2005.0468.</mixed-citation></citation-alternatives></ref><ref id="cit20"><label>20</label><citation-alternatives><mixed-citation xml:lang="ru">Huang T.-K., McDonald K.A. Bioreactor engineering for recombinant protein production in plant cell suspension cultures. Biochem. Eng. J. 2009;45:168-184. DOI 10.1016/j.bej.2009.02.008.</mixed-citation><mixed-citation xml:lang="en">Huang T.-K., McDonald K.A. Bioreactor engineering for recombinant protein production in plant cell suspension cultures. Biochem. Eng. J. 2009;45:168-184. DOI 10.1016/j.bej.2009.02.008.</mixed-citation></citation-alternatives></ref><ref id="cit21"><label>21</label><citation-alternatives><mixed-citation xml:lang="ru">Kaldis A., Ahmad A., Reid A., McGarvey B., Brandle J., Ma Sh., Jevnikar A., Kohalmi S.E., Menassa R. Highlevel production of human interleukin-10 fusions in tobacco cell suspension cultures. Plant Biotechnol. J. 2013;11:535-545. DOI 10.1111/pbi.12041.</mixed-citation><mixed-citation xml:lang="en">Kaldis A., Ahmad A., Reid A., McGarvey B., Brandle J., Ma Sh., Jevnikar A., Kohalmi S.E., Menassa R. Highlevel production of human interleukin-10 fusions in tobacco cell suspension cultures. Plant Biotechnol. J. 2013;11:535-545. DOI 10.1111/pbi.12041.</mixed-citation></citation-alternatives></ref><ref id="cit22"><label>22</label><citation-alternatives><mixed-citation xml:lang="ru">Lelivelt C., McCabe M., Newell C. Stable plastid transformation in lettuce (Lactuca sativa L.). Plant Mol. Biol. 2005;58:763-774. DOI 10.1007/s11103-005-7704-8.</mixed-citation><mixed-citation xml:lang="en">Lelivelt C., McCabe M., Newell C. Stable plastid transformation in lettuce (Lactuca sativa L.). Plant Mol. Biol. 2005;58:763-774. DOI 10.1007/s11103-005-7704-8.</mixed-citation></citation-alternatives></ref><ref id="cit23"><label>23</label><citation-alternatives><mixed-citation xml:lang="ru">Magnuson N.S., Linzmaier P.M., Reeves R., An G., Hay-Glass K., Lee J.M. Secretion of biologically active human interleukin-2 and interleukin-4 from genetically modified tobacco cells in suspension culture. Protein Expr. Purif. 1998;13:45-52. DOI 10.1006/prep.1998.0872.</mixed-citation><mixed-citation xml:lang="en">Magnuson N.S., Linzmaier P.M., Reeves R., An G., Hay-Glass K., Lee J.M. Secretion of biologically active human interleukin-2 and interleukin-4 from genetically modified tobacco cells in suspension culture. Protein Expr. Purif. 1998;13:45-52. DOI 10.1006/prep.1998.0872.</mixed-citation></citation-alternatives></ref><ref id="cit24"><label>24</label><citation-alternatives><mixed-citation xml:lang="ru">Martinez C.A., Guilietti A.M., Talou R. Research advances in plantmade flavi-virus antigens. Biotechnol. Adv. 2012;30:1493-1505. DOI 10.1016/j.biotechadv.2012.03.004.</mixed-citation><mixed-citation xml:lang="en">Martinez C.A., Guilietti A.M., Talou R. Research advances in plantmade flavi-virus antigens. Biotechnol. Adv. 2012;30:1493-1505. DOI 10.1016/j.biotechadv.2012.03.004.</mixed-citation></citation-alternatives></ref><ref id="cit25"><label>25</label><citation-alternatives><mixed-citation xml:lang="ru">Mason H.S., Haq T.A., Clements J.D., Arntzen C.J. Edible vaccine protects mice against Echerichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B-gene. Vaccine. 1998;16:13361343. DOI 10.1016/S0264-410X(98)80020-0.</mixed-citation><mixed-citation xml:lang="en">Mason H.S., Haq T.A., Clements J.D., Arntzen C.J. Edible vaccine protects mice against Echerichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B-gene. Vaccine. 1998;16:13361343. DOI 10.1016/S0264-410X(98)80020-0.</mixed-citation></citation-alternatives></ref><ref id="cit26"><label>26</label><citation-alternatives><mixed-citation xml:lang="ru">Mason H.S., Lam D.M., Arntzen C.J. Expression of hepatitis B surface antigen in transgenic plants. Proc. Natl. Acad. Sci. USA. 1992;89: 11745-11749.</mixed-citation><mixed-citation xml:lang="en">Mason H.S., Lam D.M., Arntzen C.J. Expression of hepatitis B surface antigen in transgenic plants. Proc. Natl. Acad. Sci. USA. 1992;89: 11745-11749.</mixed-citation></citation-alternatives></ref><ref id="cit27"><label>27</label><citation-alternatives><mixed-citation xml:lang="ru">Nagels B., Weterings K., Callewaert N., van Damme E.J.M. Production of plant made pharmaceuticals: from plant host to functional protein. Crit. Rev. Plant Sci. 2012;31:148-180. DOI 10.1080/ 07352689.2011.616075.</mixed-citation><mixed-citation xml:lang="en">Nagels B., Weterings K., Callewaert N., van Damme E.J.M. Production of plant made pharmaceuticals: from plant host to functional protein. Crit. Rev. Plant Sci. 2012;31:148-180. DOI 10.1080/ 07352689.2011.616075.</mixed-citation></citation-alternatives></ref><ref id="cit28"><label>28</label><citation-alternatives><mixed-citation xml:lang="ru">Permyakova N.V., Uvarova E.A., Deineko E.V. State of research in the field of the creation of plant vaccines for veterinary use. Russian Journal of Plant Physiology. 2015;62(1):23-38. DOI 10.1134/S1021443715010100.</mixed-citation><mixed-citation xml:lang="en">Permyakova N.V., Uvarova E.A., Deineko E.V. State of research in the field of the creation of plant vaccines for veterinary use. Russian Journal of Plant Physiology. 2015;62(1):23-38. DOI 10.1134/S1021443715010100.</mixed-citation></citation-alternatives></ref><ref id="cit29"><label>29</label><citation-alternatives><mixed-citation xml:lang="ru">Reinsing S., Lang D., Knight C. The Physcomitrella genome reveals evolutionary insights into the conquest of land by plants. Science. 2008;319:64-69. DOI 10.1126/science.1150646.</mixed-citation><mixed-citation xml:lang="en">Reinsing S., Lang D., Knight C. The Physcomitrella genome reveals evolutionary insights into the conquest of land by plants. Science. 2008;319:64-69. DOI 10.1126/science.1150646.</mixed-citation></citation-alternatives></ref><ref id="cit30"><label>30</label><citation-alternatives><mixed-citation xml:lang="ru">Reski R., Parsons J., Decker E.L. Moss-made pharmaceuticals: from bench to bedside. Plant Biotechnol. J. 2015;13(8):1191-1198. DOI 10.1111/pbi.12401.</mixed-citation><mixed-citation xml:lang="en">Reski R., Parsons J., Decker E.L. Moss-made pharmaceuticals: from bench to bedside. Plant Biotechnol. J. 2015;13(8):1191-1198. DOI 10.1111/pbi.12401.</mixed-citation></citation-alternatives></ref><ref id="cit31"><label>31</label><citation-alternatives><mixed-citation xml:lang="ru">Rosales-Mendoza S. Algae-Based Biopharmaceuticals. Springer, 2016. DOI 10.1007/978-3-319-32232-2.</mixed-citation><mixed-citation xml:lang="en">Rosales-Mendoza S. Algae-Based Biopharmaceuticals. Springer, 2016. DOI 10.1007/978-3-319-32232-2.</mixed-citation></citation-alternatives></ref><ref id="cit32"><label>32</label><citation-alternatives><mixed-citation xml:lang="ru">Rosales-Mendoza S., Tello-Olea M.A. Carrot cells: a pioneering platform for biopharmaceuticals production. Mol. Biotechnol. 2015;57: 219-232. DOI 10.1007/s12033-014-9837-y.</mixed-citation><mixed-citation xml:lang="en">Rosales-Mendoza S., Tello-Olea M.A. Carrot cells: a pioneering platform for biopharmaceuticals production. Mol. Biotechnol. 2015;57: 219-232. DOI 10.1007/s12033-014-9837-y.</mixed-citation></citation-alternatives></ref><ref id="cit33"><label>33</label><citation-alternatives><mixed-citation xml:lang="ru">Rybicki E.P. Plant-made vaccines for humans and animals. Plant Biotechnol. J. 2010;8:620-637. DOI 10.1111/j.1467-7652.2010.00507.x.</mixed-citation><mixed-citation xml:lang="en">Rybicki E.P. Plant-made vaccines for humans and animals. Plant Biotechnol. J. 2010;8:620-637. DOI 10.1111/j.1467-7652.2010.00507.x.</mixed-citation></citation-alternatives></ref><ref id="cit34"><label>34</label><citation-alternatives><mixed-citation xml:lang="ru">Schelkunov S.N., Salyaev R.K., Pozdnyakov S.G., Rekoslavskaya N.I., Nesterov A.E. Immunogenecity of a novel, bivalent, plantbased oral vaccine against hepatitis B and human immunodeficiency viruses. Biotechnol. Lett. 2006;28(13):959-967. DOI 10.1007/ s10529-006-9028-4.</mixed-citation><mixed-citation xml:lang="en">Schelkunov S.N., Salyaev R.K., Pozdnyakov S.G., Rekoslavskaya N.I., Nesterov A.E. Immunogenecity of a novel, bivalent, plantbased oral vaccine against hepatitis B and human immunodeficiency viruses. Biotechnol. Lett. 2006;28(13):959-967. DOI 10.1007/ s10529-006-9028-4.</mixed-citation></citation-alternatives></ref><ref id="cit35"><label>35</label><citation-alternatives><mixed-citation xml:lang="ru">Schiermeyer A., Schillberg S. Plant molecular pharming – pharmaceuticals for human health. Encyclopedia of Sustainability Science and Technology. Ed. R.A. Meyers. N. Y.: Springer, 2012;8126-8141.</mixed-citation><mixed-citation xml:lang="en">Schiermeyer A., Schillberg S. Plant molecular pharming – pharmaceuticals for human health. Encyclopedia of Sustainability Science and Technology. Ed. R.A. Meyers. N. Y.: Springer, 2012;8126-8141.</mixed-citation></citation-alternatives></ref><ref id="cit36"><label>36</label><citation-alternatives><mixed-citation xml:lang="ru">Schillberg S., Raven N., Fischer R., Twyman R., Schiermeyer A. Molecular farming of pharmaceutical proteins using plant suspension cell and tissue cultures. Curr. Pharm. Des. 2013;19:5531-5542.</mixed-citation><mixed-citation xml:lang="en">Schillberg S., Raven N., Fischer R., Twyman R., Schiermeyer A. Molecular farming of pharmaceutical proteins using plant suspension cell and tissue cultures. Curr. Pharm. Des. 2013;19:5531-5542.</mixed-citation></citation-alternatives></ref><ref id="cit37"><label>37</label><citation-alternatives><mixed-citation xml:lang="ru">Sourrouille C., Marshall B., Lienard D., Faye L. From Neanderthal to nanobiotech: From plant potions to pharming with plant factories. Ed. L. Faye, V. Gomord. Methods in Molecular Biology: Recombinant Proteins From Plants. Humana Press, a part of Springer Science+Buisness Media, 2009;1-23. DOI 10.1007/978-1-59745407-0_1.</mixed-citation><mixed-citation xml:lang="en">Sourrouille C., Marshall B., Lienard D., Faye L. From Neanderthal to nanobiotech: From plant potions to pharming with plant factories. Ed. L. Faye, V. Gomord. Methods in Molecular Biology: Recombinant Proteins From Plants. Humana Press, a part of Springer Science+Buisness Media, 2009;1-23. DOI 10.1007/978-1-59745407-0_1.</mixed-citation></citation-alternatives></ref><ref id="cit38"><label>38</label><citation-alternatives><mixed-citation xml:lang="ru">Tacket C.O., Mason H.S., Losonsky G., Estes M.K., Arntzen C.J. Human immune responses to a novel Norwalk virus vaccine delivered in transgenic potatoes. J. Infect. Dis. 2000;182:302-305. DOI 10.1086/315653.</mixed-citation><mixed-citation xml:lang="en">Tacket C.O., Mason H.S., Losonsky G., Estes M.K., Arntzen C.J. Human immune responses to a novel Norwalk virus vaccine delivered in transgenic potatoes. J. Infect. Dis. 2000;182:302-305. DOI 10.1086/315653.</mixed-citation></citation-alternatives></ref><ref id="cit39"><label>39</label><citation-alternatives><mixed-citation xml:lang="ru">Taunt H., Stoffels L., Purton S. Green biologics: The algal chloroplast as a platform for making biopharmaceuticals. Bioengineered. 2017. DOI 10.1080/21655979.2017.1377867.</mixed-citation><mixed-citation xml:lang="en">Taunt H., Stoffels L., Purton S. Green biologics: The algal chloroplast as a platform for making biopharmaceuticals. Bioengineered. 2017. DOI 10.1080/21655979.2017.1377867.</mixed-citation></citation-alternatives></ref><ref id="cit40"><label>40</label><citation-alternatives><mixed-citation xml:lang="ru">Tekoah Y., Shulman A., Kizhner T., Ruderfer I., Fux L., Nataf Y., Bartfeld D., Ariel T., Gingis-Velitski S., Hanania U., Shaaltiel Y. Large-scale production of pharmaceutical proteins in plant cell culture – the protalix experience. Plant Biotechnol. J. 2015;13:11991208. DOI 10.1111/pbi.12428.</mixed-citation><mixed-citation xml:lang="en">Tekoah Y., Shulman A., Kizhner T., Ruderfer I., Fux L., Nataf Y., Bartfeld D., Ariel T., Gingis-Velitski S., Hanania U., Shaaltiel Y. Large-scale production of pharmaceutical proteins in plant cell culture – the protalix experience. Plant Biotechnol. J. 2015;13:11991208. DOI 10.1111/pbi.12428.</mixed-citation></citation-alternatives></ref><ref id="cit41"><label>41</label><citation-alternatives><mixed-citation xml:lang="ru">Tiwari S., Verma P.C., Singh P.K., Tuli R. Plants as bioreactors for the production of vaccines and antigens. Biotechnol. Adv. 2009;27:449467. DOI 10.1016/j.biotechadv.2009.03.006.</mixed-citation><mixed-citation xml:lang="en">Tiwari S., Verma P.C., Singh P.K., Tuli R. Plants as bioreactors for the production of vaccines and antigens. Biotechnol. Adv. 2009;27:449467. DOI 10.1016/j.biotechadv.2009.03.006.</mixed-citation></citation-alternatives></ref><ref id="cit42"><label>42</label><citation-alternatives><mixed-citation xml:lang="ru">Twyman R.M., Stoger E., Schillberg S., Christou P., Fischer R. Molecular farming in plants: host systems and expression technology. Trends Biotechnol. 2003;21:570-578. DOI 10.1016/j.tibtech.2003.10.002.</mixed-citation><mixed-citation xml:lang="en">Twyman R.M., Stoger E., Schillberg S., Christou P., Fischer R. Molecular farming in plants: host systems and expression technology. Trends Biotechnol. 2003;21:570-578. DOI 10.1016/j.tibtech.2003.10.002.</mixed-citation></citation-alternatives></ref><ref id="cit43"><label>43</label><citation-alternatives><mixed-citation xml:lang="ru">Weise A., Altmann F.M., Rodriguez-Franco M. High level expression of secreted complex glycosylated recombinant human erythropoietin in the Physcomitrella delta-fuc-t and delta-xyl-t mutant. Plant Biotechnol. J. 2007;5:389-401. DOI 10.1111/j.14677652.2007.00248.x.</mixed-citation><mixed-citation xml:lang="en">Weise A., Altmann F.M., Rodriguez-Franco M. High level expression of secreted complex glycosylated recombinant human erythropoietin in the Physcomitrella delta-fuc-t and delta-xyl-t mutant. Plant Biotechnol. J. 2007;5:389-401. DOI 10.1111/j.14677652.2007.00248.x.</mixed-citation></citation-alternatives></ref><ref id="cit44"><label>44</label><citation-alternatives><mixed-citation xml:lang="ru">Yusibov V., Rabindran S. Resent progress in the development of plant-derived vaccines. Expert Rev. Vaccin. 2008;7:1173-1183. DOI 10.1586/14760584.7.8.1173.</mixed-citation><mixed-citation xml:lang="en">Yusibov V., Rabindran S. Resent progress in the development of plant-derived vaccines. Expert Rev. Vaccin. 2008;7:1173-1183. DOI 10.1586/14760584.7.8.1173.</mixed-citation></citation-alternatives></ref><ref id="cit45"><label>45</label><citation-alternatives><mixed-citation xml:lang="ru">Yusibov V., Streatfield S., Kushnir N. Clinical development of plant-produced recombinant pharmaceuticls. Hum. Vaccin. 2011;7(3):313-321. DOI 10.4161/hv.7.3.14207.</mixed-citation><mixed-citation xml:lang="en">Yusibov V., Streatfield S., Kushnir N. Clinical development of plant-produced recombinant pharmaceuticls. Hum. Vaccin. 2011;7(3):313-321. DOI 10.4161/hv.7.3.14207.</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
