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Plant Molecular Farming: A Viable Platform for Recombinant Biopharmaceutical Production

Balamurugan Shanmugaraj, Christine Joy I. Bulaon, Waranyoo Phoolcharoen

Plants · 2020 · Review · CC BY

doi:10.3390/plants9070842

Abstract

The demand for recombinant proteins in terms of quality, quantity, and diversity is increasing steadily, which is attracting global attention for the development of new recombinant protein production technologies and the engineering of conventional established expression systems based on bacteria or mammalian cell cultures. Since the advancements of plant genetic engineering in the 1980s, plants have been used for the production of economically valuable, biologically active non-native proteins or biopharmaceuticals, the concept termed as plant molecular farming (PMF). PMF is considered as a cost-effective technology that has grown and advanced tremendously over the past two decades. The development and improvement of the transient expression system has significantly reduced the protein production timeline and greatly improved the protein yield in plants. The major factors that drive the plant-based platform towards potential competitors for the conventional expression system are cost-effectiveness, scalability, flexibility, versatility, and robustness of the system. Many biopharmaceuticals including recombinant vaccine antigens, monoclonal antibodies, and other commercially viable proteins are produced in plants, some of which are in the pre-clinical and clinical pipeline. In this review, we consider the importance of a plant- based production system for recombinant protein production, and its potential to produce biopharmaceuticals is discussed.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 22, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Recombinant proteins are complex exogenous (“foreign”) proteins that are produced in expression hosts, and mainly used as medical diagnostic reagents and in human healthcare as vaccines, drugs, or monoclonal antibodies. The prominent role and increasing market demand for high-value recombinant proteins in novel drug discovery creates an opportunity for the development of various protein expression hosts to manufacture proteins by following the existing rigid standards laid down for veterinary and human applications. The industry is focusing mainly on already established production platforms using prokaryotic and eukaryotic expression host systems such as Escherichia coli, a selection of yeast, insect, and mammalian cell cultures, due to their well-defined processes in-line with current good manufacturing practice (cGMP). Moreover, industrially established mammalian and other cell cultures have stringent regulatory approval in place, which hinders the industrial acceptance of the new technology or production system. Bacterial expression systems offer rapid production with high product yield, whereas Saccharomyces cerevisiae and Pichia pastoris (yeast) offer post-translational modifications (PTMs) which are essential for functional activity of the recombinant proteins. The majority of the approved recombinant biopharmaceuticals are produced in mammalian cell lines. However, all the production systems have their own merits and setbacks such as production time, high operating costs, protein yield, chances of contamination with pathogenic microorganisms, limited post-translational modifications, and regulatory approval. In order to compete with the established platform, the new expression system must have unique advantages that can overcome the limitations of the existing ones. Plants offer several potential benefits over conventional expression platforms and prove the reliability of the system for the production of highly valuable proteins. Advancements in plant molecular farming approaches in the recent decade have made plants an attractive manufacturing system that can even achieve commercially relevant production levels in a short period. As the progress is continuously being made in this ever-growing field, here in this review, we summarize the importance and prospects of plant expression systems for the cost-effective production of recombinant proteins. Potential vaccine candidates, monoclonal antibodies, and industrial enzymes expressed in plants are also described.

2. Plant Expression Platform

Plants were utilized for the expression of recombinant proteins from the late 1980s. Since then, the plant expression platform has faced several hurdles, until recently the first plant-based product “Elelyso” was commercialized by Protalix Biotherapeutics for the treatment of Gaucher’s disease in 2012. The practice of using plants for high-value recombinant protein production ranging from pharmaceutical therapeutics to non-pharmaceutical products such as antibodies, vaccine antigens, enzymes, growth factors, research or diagnostic reagents, and cosmetic ingredients has improved over time and advanced significantly in recent decades, which in turn has led to a major paradigm shift in the pharmaceutical sector. The technology has rapidly developed, and the potential drawbacks associated with plant molecular farming during their early stages of development, including the need for a high protein expression level and efficient downstream processing, have now been achieved. The advantages of plant expression platforms are cited in several earlier reports showing head-to-head comparisons with other existing platforms (Table 1). The key advantages of all plant-based systems are easy cultivation, low expenses, low or no pathogen load, rapid mass production of recombinant proteins, and the ability of the plants to assemble complex proteins with eukaryotic-like post-translational modifications (PTMs).

Protein folding is highly essential to retain the biological activity of the recombinant therapeutic proteins. Due to the lack of the protein processing complex and limited capacity for PTMs, proper protein folding cannot be achieved in the prokaryotic expression system. Plants have the capacity to assemble and perform PTMs of large multimeric proteins required for their functional biological activity. However, plants lack the authentic human N-glycosylation processing mechanism which has been overcome by the glycoengineering approaches towards the synthesis of targeted human and non-human structures to increase product homogeneity, quality, and quantity.

The Nicotiana genus is often used for genetic transformation studies due to its growth rate and easy genetic manipulation. Most of the recombinant proteins such as pharmaceuticals, vaccines, hormones, cytokines, growth regulators, and industrial products are produced in tobacco, which is considered as a molecular biology workhouse of the plant world. Nicotiana benthamiana and N. tabacum are two common species used for the stable and transient expression of recombinant proteins. Further, several cereal crops, fruits, and vegetables such as rice, maize, lettuce, tomato, potato, and alfalfa were also evaluated for their applicability in plant molecular farming (PMF) depending on the protein target and application. Many plant-produced therapeutic proteins are in pre-clinical and clinical trials and are close to commercialization. The strength and bottlenecks of the commercial potential of the plant expression system was critically reviewed and summarized by Schillberg et al. (2019).

3. Plant-Derived Recombinant Proteins

The concept of using plants for the production of foreign proteins including pharmaceutical and non-pharmaceutical proteins has been well explored and documented. Many reports proved the ability of in vivo and in vitro plant systems to produce vaccine candidates both for veterinary and human applications and showed that plant-produced antigens elicit potential immune responses in animal models and even confer protection in animal challenge experiments. Examples of the variety of pharmaceutical and non-pharmaceutical proteins expressed in plant systems are illustrated in Table 2 and Table 3.

Tobacco has been engineered to express a variety of antigens in the nucleus and chloroplast including, but not limited to, chikungunya, dengue, Ebola, influenza, and Zika. The transformation protocols for recombinant protein production are also established for fruits and vegetables such as tomatoes and potatoes. Transgenic potatoes expressing the S1 glycoprotein of the infectious bronchitis virus confers protection to chickens upon virus challenge. Leafy crops such as lettuce, alfalfa, and clover have been investigated for molecular farming to obtain the oral delivery of vaccine antigens eliminating purification and injections. The lettuce chloroplast-derived booster vaccine using lyophilized plant cells expressing the poliovirus capsid protein induced neutralization antibodies in mice primed with inactivated poliovirus vaccine (IPV) and conferred protection against all polio serotypes. Plant systems have also been evaluated for the expression of virus-like particles (VLP) of many viruses including norovirus, poliovirus, foot-and-mouth disease virus, influenza,, and the potential for plant-derived VLPs to be used as candidate vaccines and reagents has been reviewed in detail elsewhere. Apart from expressing antigens for human diseases, several antigens for veterinary applications and non-pharmaceutical proteins have also been well tested for expression in plants, and are particularly gaining attention due to the fact that these products can quickly reach the market due to lower regulatory burden. This was clearly evidenced by the commercialization of avidin, β-glucuronidase, and trypsin by the US-based biotechnology company ProdiGene, Inc. The vaccine against Newcastle disease virus (NDV) was the first plant-based poultry vaccine (Dow Agrosciences) that obtained regulatory approval from the United States Department of Agriculture in 2006, opening a new avenue for the commercialization of plant-derived vaccines. Currently, many plant-derived non-pharmaceutical and pharmaceutical proteins are in clinical development.

Although proof-of-concept and efficacy of many vaccine candidates proved the feasibility and scalability of the robust plant system, it is high time to compete with the established expression systems. Now the plant-based good manufacturing practices (GMP) complaint production facilities such as Fraunhofer (Germany), Kentucky BioProcessing (USA), Medicago (Canada), and Protalix Biotherapeutics (Israel) are available to manufacture GMP materials for human clinical trials. Fraunhofer IME received a GMP license for the production of neutralizing anti-HIV antibody 2G12 in tobacco for phase I clinical testing. The plant molecular farming research community continuously thrives to set up a regulatory framework for plant-derived products.

4. Strategies Used for Recombinant Protein Production in Plants

The expression methods used for the recombinant protein production in plants can be either stable or transient expression. PMF relies on following approaches for the expression of vaccine candidates, i.e., stable nuclear transformation, stable chloroplast transformation, or transient expression, by using plant viral vectors and stable transformation of hydroponically grown plants in which recombinant proteins are recovered from the medium (Figure 1).

Stable nuclear transformation is the traditional strategy of genetic manipulation in plants for recombinant protein production. The transgene in the plant expression vector can be introduced into the in vitro grown plantlets either with Agrobacterium tumefaciens-mediated transformation or particle bombardment, and stable transgenic lines can be developed. The best transgenic line for protein production will be subsequently screened from the pool of transgenic lines. By this method, recombinant proteins can be produced in successive generations, as the transgene has been stably integrated into the plant genome. The model plants such as Arabidopsis thaliana and tobacco were more commonly used during the early stages of genetic transformation to develop stable transformants. Stable transformation in plants requires substantial time and is a labor-intensive process, and the protein expression is insufficient to meet the industrial-level protein production. However, the antigen expression in stable transgenic line could be used for developing oral vaccines that could reduce the cost associated with protein purification.

Alternatively, transient expression based on agroinfiltration or virus-based vectors have been developed to complement transgenic plants that offer rapid and high-level protein expression within a few days. The drawbacks and challenges associated with stable expression, such as insufficient protein expression, time, and consistency, have been overcome by the development of novel strategies involving deconstructed viral vector systems such as MagnICON® technology, geminiviral, and pEAQ, which allows rapid accumulation of recombinant proteins in a short time. Hence, it is considered as a suitable convenient platform, especially for the production of vaccine antigens or monoclonal antibodies against infectious diseases (Figure 2). Gleba et al. (2007) summarized the application of plant viral vectors for the transient expression of heterologous proteins in plants. Plant transient expression holds tremendous potential to produce rapid-response proteins, emergency vaccines, or biologics, which was impressively shown during the Ebola outbreak in 2014. Mapp Biopharmaceutical Inc., USA produced an experimental drug ZMapp, an anti-Ebola antibody cocktail of three chimeric monoclonal antibodies manufactured in tobacco plants (Nicotiana benthamiana) to treat humans during the recent Ebola outbreak. During a pandemic situation, in order to cope with a rapidly spreading infectious disease, production methods should meet the demand for production targets of strategic vaccines to control the disease. One of the recent examples is the pandemic, corona virus disease (COVID-19). The virus has spread rapidly, and millions of people have been affected across 6 continents in few months, posing a constant threat to global health. This infection has created a massive demand for diagnostic reagents, vaccines, and therapeutic development. Given the speed advantages, and proven viability of the plant production platform, the transient expression system in particular could be employed to produce recombinant proteins at high levels to meet the sudden demand for production of viral antigens or antiviral proteins that could be used as research reagents, emergency vaccines (SARS-CoV-2 subunit and virus-like particle vaccines), or other biopharmaceuticals to fight against COVID-19. The neutralizing monoclonal antibodies against SARS-CoV-2 could also be produced in plants with minimal investment, which could be used for passive immunotherapy. Recently, Medicago (Quebec, Canada), Kentucky BioProcessing (Owensboro, KT, USA), and iBio (Bryan, TX, USA) joined the global race for developing potential plant-based vaccines for COVID-19. By using the transient expression platform, recombinant protein production in plants could be scaled up rapidly, and milligram quantities of proteins could be produced in a timeframe of less than 4 weeks after receiving the corresponding gene construct.

Alternately, chloroplast expression focuses on expressing the transgenes in chloroplast by the precise insertion of foreign DNA by homologous recombination into the chloroplast genome. Much progress has been made in chloroplast engineering in recent years. The transformation of the chloroplast genome has many advantages over nuclear transformation which includes higher protein production, lack of gene silencing and position effect, polycistronic mRNA expression, and prevention of transmission of foreign DNA through pollen by uniparental plastid gene inheritance (maternal inheritance) in crop plants.

Similar to bacterial and mammalian cells, heterologous protein production can be achieved by using individual suspension of plant cells rather than whole plants. The cell suspension derived from undifferentiated callus grown in liquid medium can be scaled up in bioreactors for large-scale protein production under an aseptic environment. The first USDA-approved poultry vaccine and the first FDA-approved recombinant plant-produced pharmaceutical protein “Elelyso” were produced in tobacco and carrot cell suspension cultures, respectively, which proved the importance and competitiveness of plant suspension culture in high-value protein production in the biopharmaceutical industry. Hairy root cultures are also being explored as an alternative recombinant protein production system due to their ease in protein recovery and low costs. The recombinant proteins are secreted from the transgenic plant roots into the culture medium viz., rhizosecretion; hence, this allows continuous protein production and recovery from the culture medium without the requirement of cell lysis during extraction. Moreover, recombinant proteins produced from root cultures attribute to the improved protein quality and quantity without complex downstream processing that could eventually reduce production costs as well. A recent review on the applications of hairy root cultures for protein production has been extensively discussed by Gutierrez–Valdes et al. (2020).

5. Perspectives

Although plants are attractive with several unique advantages, they are unable to compete with the existing microbial and mammalian systems, as both are well established and characterized, especially in terms of GMP manufacturing and regulatory approval in an industrial setting. Even after many years of research, which has shown the proof-of-concept of expressing many therapeutic proteins in plants, the process of producing therapeutic proteins from the lab bench to commercialization is slow. Hence, in order to move forward, the commercial potential and economic sustainability of technology needs to be exploited by developing veterinary vaccines, non-pharmaceutical diagnostic, cosmetic products, and industrial enzymes in plants, as they have a low regulatory burden compared to therapeutic proteins. This technology can also be employed to reproduce rapid response vaccines or diagnostic reagents against emerging infections. For the past few years, extensive research has been carried out to combat the several emerging diseases including Zika, chikungunya, Nipah, SARS-CoV, MERS-CoV, and more recently SARS-CoV-2. Even though several efforts have been made for many years to develop effective vaccine candidates for many of those emerging and zoonotic diseases, still, there are no vaccine candidates or therapeutic measures available commercially. Even if a successful vaccine or drug developed against such diseases, it is unlikely that it would have a significant impact on developing and under-developed countries, due to the high cost associated with it, and scalability concern. In such a scenario, a plant-derived vaccine or diagnostic reagent would be a feasible approach to rapidly respond to the demand and need for recombinant proteins. However, harnessing the full potential of this plant molecular farming technology for cost-effective vaccines or drug development will be evident in the upcoming years.

6. Conclusions

Plants have both economic and technical advantages over conventional expression systems for the production of pharmaceutical and non-pharmaceutical products. The different PMF technologies such as nuclear, chloroplast expression, viral transfection, and transient expression systems have their unique features, enabling them to address a production of diversified product “targets” with less production constraints in a short time. Many scientific and technical challenges associated with the plant platform were met in recent years. However, the regulatory burden associated with therapeutic protein production is a major barrier that hinders the widespread acceptance of the plant system. Considering the low costs and greater scalability of plant production systems, the commercialization of non-pharmaceutical proteins is straightforward and faster due to lower regulatory challenges. Hence, the universal acceptance of the technology will be strongly influenced by the regulatory framework and restrictions applied to plant-derived products worldwide. The demand for industrially or pharmaceutically useful recombinant proteins, together with demonstrated production capability and economic feasibility of the plant system, suggests a bright future for the plant-made biologics.

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    D’Aoust M.-A., Lavoie P.-O., Couture M.M.-J., Trépanier S., Guay J.-M., Dargis M., Mongrand S., Landry N., Ward B.J., Vézina L.-P. Influenza virus-like particles produced by transient expression in Nicotiana benthamiana induce a protective immune response against a lethal viral challenge in mice. Plant Biotechnol. J. 2008;6:930-940.

    Not in our library10.1111/j.1467-7652.2008.00384.x

  53. 53.

    Rosales-Mendoza S., Soria-Guerra R.E., Lopez-Revilla R., Moreno-Fierros L., Alpuche-Solis A.G. Ingestion of transgenic carrots expressing the Escherichia coli heat-labile enterotoxin B subunit protects mice against cholera toxin challenge. Plant Cell Rep. 2008;27:79-84.

    Not in our library10.1007/s00299-007-0439-z

  54. 54.

    Santi L., Batchelor L., Huang Z., Hjelm B., Kilbourne J., Arntzen C.J., Chen Q., Mason H.S. An efficient plant viral expression system generating orally immunogenic Norwalk virus-like particles. Vaccine. 2008;26:1846-1854.

    Not in our library10.1016/j.vaccine.2008.01.053

  55. 55.

    Wang D.M., Zhu J.B., Peng M., Zhou P. Induction of a protective antibody response to FMDV in mice following oral immunization with transgenic Stylosanthes spp. as a feedstuff additive. Transgenic Res. 2008;17:1163-1170.

    Not in our library10.1007/s11248-008-9188-1

  56. 56.

    Scotti N., Alagna F., Ferraiolo E., Formisano G., Sannino L., Buonaguro L., De Stradis A., Vitale A., Monti L., Grillo S., et al. High-level expression of the HIV-1 Pr55gag polyprotein in transgenic tobacco chloroplasts. Planta. 2009;229:1109-1122.

    Not in our library10.1007/s00425-009-0898-2

  57. 57.

    Wang Y., Deng H., Zhang X., Xiao H., Jiang Y., Song Y., Fang L., Xiao S., Zhen Y., Chen H. Generation and immunogenicity of Japanese encephalitis virus envelope protein expressed in transgenic rice. Biochem. Biophys. Res. Commun. 2009;380:292-297.

    Not in our library10.1016/j.bbrc.2009.01.061

  58. 58.

    Kalthoff D., Giritch A., Geisler K., Bettmann U., Klimyuk V., Hehnen H.R., Gleba Y., Beer M. Immunization with plant-expressed hemagglutinin protects chickens from lethal highly pathogenic avian influenza virus H5N1 challenge infection. J. Virol. 2010;84:12002-12010.

    Not in our library10.1128/jvi.00940-10

  59. 59.

    Shoji Y., Farrance C.E., Bautista J., Bi H., Musiychuk K., Horsey A., Park H., Jaje J., Green B.J., Shamloul M., et al. A plant-based system for rapid production of influenza vaccine antigens. Influenza Other Respir. Viruses. 2012;6:204-210.

    Not in our library10.1111/j.1750-2659.2011.00295.x

  60. 60.

    Kanagarajan S., Tolf C., Lundgren A., Waldenstrom J., Brodelius P.E. Transient expression of hemagglutinin antigen from low pathogenic avian influenza A (H7N7) in Nicotiana benthamiana. PLoS ONE. 2012;7:e33010.

    Not in our library10.1371/journal.pone.0033010

  61. 61.

    Gómez E., Lucero M.S., Chimeno Zoth S., Carballeda J.M., Gravisaco M.J., Berinstein A. Transient expression of VP2 in Nicotiana benthamiana and its use as a plant-based vaccine against Infectious Bursal Disease Virus. Vaccine. 2013;31:2623-2627.

    Not in our library10.1016/j.vaccine.2013.03.064

  62. 62.

    Perez Aguirreburualde M.S., Gomez M.C., Ostachuk A., Wolman F., Albanesi G., Pecora A., Odeon A., Ardila F., Escribano J.M., Dus Santos M.J., et al. Efficacy of a BVDV subunit vaccine produced in alfalfa transgenic plants. Vet. Immunol. Immunopathol. 2013;151:315-324.

    Not in our library10.1016/j.vetimm.2012.12.004

  63. 63.

    Thuenemann E.C., Meyers A.E., Verwey J., Rybicki E.P., Lomonossoff G.P. A method for rapid production of heteromultimeric protein complexes in plants: Assembly of protective bluetongue virus-like particles. Plant Biotechnol. J. 2013;11:839-846.

    Not in our library10.1111/pbi.12076

  64. 64.

    Mathew L.G., Herbst-Kralovetz M.M., Mason H.S. Norovirus Narita 104 virus-like particles expressed in Nicotiana benthamiana induce serum and mucosal immune responses. Biomed. Res. Int. 2014;2014:807539.

    Not in our library10.1155/2014/807539

  65. 65.
    Boosting in planta production of antigens derived from the porcine reproductive and respiratory syndrome virus (PRRSV) and subsequent evaluation of their immunogenicity. · 2014
    Not checked
  66. 66.

    Firsov A., Tarasenko I., Mitiouchkina T., Ismailova N., Shaloiko L., Vainstein A., Dolgov S. High-yield expression of M2e peptide of Avian Influenza virus H5N1 in transgenic duckweed plants. Mol. Biotechnol. 2015;57:653-661.

    Not in our library10.1007/s12033-015-9855-4

  67. 67.

    Mbewana S., Mortimer E., Pera F.F., Hitzeroth I.I., Rybicki E.P. Production of H5N1 influenza virus matrix protein 2 ectodomain protein bodies in tobacco plants and in insect cells as a candidate universal influenza vaccine. Front. Bioeng. Biotechnol. 2015;3:197.

    Not in our library10.3389/fbioe.2015.00197

  68. 68.

    Kim M.-Y., Jang Y.-S., Yang M.-S., Kim T.-G. High expression of consensus dengue virus envelope glycoprotein domain III using a viral expression system in tobacco. Plant Cell Tissue Organ Cult. 2015;122:445-451.

    Not in our library10.1007/s11240-015-0781-8

  69. 69.

    Gottschamel J., Lössl A., Ruf S., Wang Y., Skaugen M., Bock R., Clarke J.L. Production of dengue virus envelope protein domain III-based antigens in tobacco chloroplasts using inducible and constitutive expression systems. Plant Mol. Biol. 2016;91:497-512.

    Not in our library10.1007/s11103-016-0484-5

  70. 70.

    Kota S., Subramanian M., Shanmugaraj B., Challa H., Ponanna N.M. Subunit vaccine based on plant expressed recombinant Eimeria gametocyte antigen Gam82 elicit protective immune response against chicken coccidiosis. J. Vaccines Vaccin. 2017;8.

    Not in our library10.4172/2157-7560.1000374

  71. 71.

    Iyappan G., Shanmugaraj B.M., Inchakalody V., Ma J.K.C., Ramalingam S. Potential of plant biologics to tackle the epidemic like situations—Case studies involving viral and bacterial candidates. Int. J. Infect. Dis. 2018;73:363.

    Not in our library10.1016/j.ijid.2018.04.4236

  72. 72.

    Yang M., Sun H., Lai H., Hurtado J., Chen Q. Plant-produced Zika virus envelope protein elicits neutralizing immune responses that correlate with protective immunity against Zika virus in mice. Plant Biotechnol. J. 2018;16:572-580.

    Not in our library10.1111/pbi.12796

  73. 73.

    Gunter C.J., Regnard G.L., Rybicki E.P., Hitzeroth I.I. Immunogenicity of plant-produced porcine circovirus-like particles in mice. Plant Biotechnol. J. 2019;17:1751-1759.

    Not in our library10.1111/pbi.13097

  74. 74.

    Margolin E., Chapman R., Meyers A.E., van Diepen M.T., Ximba P., Hermanus T., Crowther C., Weber B., Morris L., Williamson A.L., et al. Production and immunogenicity of soluble plant-produced HIV-1 subtype C envelope gp140 immunogens. Front. Plant Sci. 2019;10:1378.

    Not in our library10.3389/fpls.2019.01378

  75. 75.

    Vaquero C., Sack M., Chandler J., Drossard J., Schuster F., Monecke M., Schillberg S., Fischer R. Transient expression of a tumor-specific single-chain fragment and a chimeric antibody in tobacco leaves. Proc. Natl. Acad. Sci. USA. 1999;96:11128-11133.

    Not in our library10.1073/pnas.96.20.11128

  76. 76.

    Torres E., Vaquero C., Nicholson L., Sack M., Stöger E., Drossard J., Christou P., Fischer R., Perrin Y. Rice cell culture as an alternative production system for functional diagnostic and therapeutic antibodies. Transgenic Res. 1999;8:441-449.

    Not in our library10.1023/a:1008969031219

  77. 77.

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

    Not in our library10.1023/a:1006301519427

  78. 78.

    Brodzik R., Glogowska M., Bandurska K., Okulicz M., Deka D., Ko K., van der Linden J., Leusen J.H., Pogrebnyak N., Golovkin M., et al. Plant-derived anti-Lewis Y mAb exhibits biological activities for efficient immunotherapy against human cancer cells. Proc. Natl. Acad. Sci. USA. 2006;103:8804-8809.

    Not in our library10.1073/pnas.0603043103

  79. 79.

    Floss D.M., Sack M., Stadlmann J., Rademacher T., Scheller J., Stöger E., Fischer R., Conrad U. Biochemical and functional characterization of anti-HIV antibody–ELP fusion proteins from transgenic plants. Plant Biotechnol. J. 2008;6:379-391.

    Not in our library10.1111/j.1467-7652.2008.00326.x

  80. 80.

    Sainsbury F., Lomonossoff G.P. Extremely high-level and rapid transient protein production in plants without the use of viral replication. Plant Physiol. 2008;148:1212-1218.

    Not in our library10.1104/pp.108.126284

  81. 81.

    Holland T., Sack M., Rademacher T., Schmale K., Altmann F., Stadlmann J., Fischer R., Hellwig S. Optimal nitrogen supply as a key to increased and sustained production of a monoclonal full-size antibody in BY-2 suspension culture. Biotechnol. Bioeng. 2010;107:278-289.

    Not in our library10.1002/bit.22800

  82. 82.

    Huang Z., Phoolcharoen W., Lai H., Piensook K., Cardineau G., Zeitlin L., Whaley K.J., Arntzen C.J., Mason H.S., Chen Q. High-level rapid production of full-size monoclonal antibodies in plants by a single-vector DNA replicon system. Biotechnol. Bioeng. 2010;106:9-17.

    Not in our library10.1002/bit.22652

  83. 83.

    Lai H., He J., Engle M., Diamond M.S., Chen Q. Robust production of virus-like particles and monoclonal antibodies with geminiviral replicon vectors in lettuce. Plant Biotechnol. J. 2012;10:95-104.

    Not in our library10.1111/j.1467-7652.2011.00649.x

  84. 84.

    So Y., Lee K.-J., Kim D.-S., Lee J.-H., Oh D.-B., Hwang K.-A., Ko K., Choo Y.-K., Ko K. Glycomodification and characterization of anti-colorectal cancer immunotherapeutic monoclonal antibodies in transgenic tobacco. Plant Cell Tissue Organ Cult. 2013;113:41-49.

    Not in our library10.1007/s11240-012-0249-z

  85. 85.

    Zeitlin L., Bohorov O., Bohorova N., Hiatt A., Kim D.H., Pauly M.H., Velasco J., Whaley K.J., Barnard D.L., Bates J.T., et al. Prophylactic and therapeutic testing of Nicotiana-derived RSV-neutralizing human monoclonal antibodies in the cotton rat model. MAbs. 2013;5:263-269.

    Not in our library10.4161/mabs.23281

  86. 86.

    Van Dolleweerd C.J., Teh A.Y., Banyard A.C., Both L., Lotter-Stark H.C., Tsekoa T., Phahladira B., Shumba W., Chakauya E., Sabeta C.T., et al. Engineering, expression in transgenic plants and characterisation of E559, a rabies virus-neutralising monoclonal antibody. J. Infect. Dis. 2014;210:200-208.

    Not in our library10.1093/infdis/jiu085

  87. 87.

    Lai H., He J., Hurtado J., Stahnke J., Fuchs A., Mehlhop E., Gorlatov S., Loos A., Diamond M.S., Chen Q. Structural and functional characterization of an anti-West Nile virus monoclonal antibody and its single-chain variant produced in glycoengineered plants. Plant Biotechnol. J. 2014;12:1098-1107.

    Not in our library10.1111/pbi.12217

  88. 88.

    Dent M., Hurtado J., Paul A.M., Sun H., Lai H., Yang M., Esqueda A., Bai F., Steinkellner H., Chen Q. Plant-produced anti-dengue virus monoclonal antibodies exhibit reduced antibody-dependent enhancement of infection activity. J. Gen. Virol. 2016;97:3280-3290.

    Not in our library10.1099/jgv.0.000635

  89. 89.

    Vamvaka E., Twyman R.M., Murad A.M., Melnik S., Teh A.Y.-H., Arcalis E., Altmann F., Stoger E., Rech E., Ma J.K.C., et al. Rice endosperm produces an underglycosylated and potent form of the HIV-neutralizing monoclonal antibody 2G12. Plant Biotechnol. J. 2016;14:97-108.

    Not in our library10.1111/pbi.12360

  90. 90.

    Shafaghi M., Maktoobian S., Rasouli R., Howaizi N., Ofoghi H., Ehsani P. Transient expression of biologically active anti-rabies virus monoclonal antibody in tobacco leaves. Iran. J. Biotechnol. 2018;16:e1774.

    Not in our library10.21859/ijb.1774

  91. 91.

    Rattanapisit K., Chao Z., Siriwattananon K., Huang Z., Phoolcharoen W. Plant-produced anti-enterovirus 71 (EV71) monoclonal antibody efficiently protects mice against EV71 infection. Plants. 2019;8:560.

    Not in our library10.3390/plants8120560

  92. 92.

    Rattanapisit K., Phakham T., Buranapraditkun S., Siriwattananon K., Boonkrai C., Pisitkun T., Hirankarn N., Strasser R., Abe Y., Phoolcharoen W. Structural and in vitro functional analyses of novel plant-produced anti-human PD1 antibody. Sci. Rep. 2019;9:15205.

    Not in our library10.1038/s41598-019-51656-1

  93. 93.

    Diamos A.G., Hunter J.G.L., Pardhe M.D., Rosenthal S.H., Sun H., Foster B.C., DiPalma M.P., Chen Q., Mason H.S. High level production of monoclonal antibodies using an optimized plant expression system. Front. Bioeng. Biotechnol. 2019;7:472.

    Not in our library10.3389/fbioe.2019.00472

  94. 94.

    Hurtado J., Acharya D., Lai H., Sun H., Kallolimath S., Steinkellner H., Bai F., Chen Q. In vitro and in vivo efficacy of anti-chikungunya virus monoclonal antibodies produced in wild-type and glycoengineered Nicotiana benthamiana plants. Plant Biotechnol. J. 2020;18:266-273.

    Not in our library10.1111/pbi.13194

  95. 95.

    Sijmons P.C., Dekker B.M., Schrammeijer B., Verwoerd T.C., van den Elzen P.J., Hoekema A. Production of correctly processed human serum albumin in transgenic plants. Biotechnology. 1990;8:217-221.

    Not in our library10.1038/nbt0390-217

  96. 96.

    Matsumoto S., Ikura K., Ueda M., Sasaki R. Characterization of a human glycoprotein (erythropoietin) produced in cultured tobacco cells. Plant Mol. Biol. 1995;27:1163-1172.

    Not in our library10.1007/bf00020889

  97. 97.

    Terashima M., Murai Y., Kawamura M., Nakanishi S., Stoltz T., Chen L., Drohan W., Rodriguez R.L., Katoh S. Production of functional human α1-antitrypsin by plant cell culture. Appl. Microbiol. Biotechnol. 1999;52:516-523.

    Not in our library10.1007/s002530051554

  98. 98.

    Zhong G.-Y., Peterson D., Delaney D.E., Bailey M., Witcher D.R., Register Iii J.C., Bond D., Li C.-P., Marshall L., Kulisek E., et al. Commercial production of aprotinin in transgenic maize seeds. Mol. Breed. 1999;5:345-356.

    Not in our library10.1023/a:1009677809492

  99. 99.

    Komarnytsky S., Borisjuk N.V., Borisjuk L.G., Alam M.Z., Raskin I. Production of recombinant proteins in tobacco guttation fluid. Plant Physiol. 2000;124:927-934.

    Not in our library10.1104/pp.124.3.927

  100. 100.

    Ruggiero F., Exposito J.Y., Bournat P., Gruber V., Perret S., Comte J., Olagnier B., Garrone R., Theisen M. Triple helix assembly and processing of human collagen produced in transgenic tobacco plants. FEBS Lett. 2000;469:132-136.

    Not in our library10.1016/s0014-5793(00)01259-x

  101. 101.

    Staub J.M., Garcia B., Graves J., Hajdukiewicz P.T., Hunter P., Nehra N., Paradkar V., Schlittler M., Carroll J.A., Spatola L., et al. High-yield production of a human therapeutic protein in tobacco chloroplasts. Nat. Biotechnol. 2000;18:333-338.

    Not in our library10.1038/73796

  102. 102.

    De Cosa 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.

    Not in our library10.1038/83559

  103. 103.

    Fernandez-San Millan A., Mingo-Castel A., Miller M., Daniell H. A chloroplast transgenic approach to hyper-express and purify Human Serum Albumin, a protein highly susceptible to proteolytic degradation. Plant Biotechnol. J. 2003;1:71-79.

    Not in our library10.1046/j.1467-7652.2003.00008.x

  104. 104.

    Wirth S., Calamante G., Mentaberry A., Bussmann L., Lattanzi M., Barañao L., Bravo-Almonacid F. Expression of active human epidermal growth factor (hEGF) in tobacco plants by integrative and non-integrative systems. Mol. Breed. 2004;13:23-35.

    Not in our library10.1023/b:molb.0000012329.74067.ca

  105. 105.

    Ding S.H., Huang L.Y., Wang Y.D., Sun H.C., Xiang Z.H. High-level expression of basic fibroblast growth factor in transgenic soybean seeds and characterization of its biological activity. Biotechnol. Lett. 2006;28:869-875.

    Not in our library10.1007/s10529-006-9018-6

  106. 106.

    Arlen P.A., Falconer R., Cherukumilli S., Cole A., Cole A.M., Oishi K.K., Daniell H. Field production and functional evaluation of chloroplast-derived interferon-alpha2b. Plant Biotechnol. J. 2007;5:511-525.

    Not in our library10.1111/j.1467-7652.2007.00258.x

  107. 107.

    Kim T.G., Baek M.Y., Lee E.K., Kwon T.H., Yang M.S. Expression of human growth hormone in transgenic rice cell suspension culture. Plant Cell Rep. 2008;27:885-891.

    Not in our library10.1007/s00299-008-0514-0

  108. 108.

    Oey M., Lohse M., Kreikemeyer B., Bock R. Exhaustion of the chloroplast protein synthesis capacity by massive expression of a highly stable protein antibiotic. Plant J. 2009;57:436-445.

    Not in our library10.1111/j.1365-313x.2008.03702.x

  109. 109.

    Xu J., Okada S., Tan L., Goodrum K.J., Kopchick J.J., Kieliszewski M.J. Human growth hormone expressed in tobacco cells as an arabinogalactan-protein fusion glycoprotein has a prolonged serum life. Transgenic Res. 2010;19:849-867.

    Not in our library10.1007/s11248-010-9367-8

  110. 110.

    An N., Ou J., Jiang D., Zhang L., Liu J., Fu K., Dai Y., Yang D. Expression of a functional recombinant human basic fibroblast growth factor from transgenic rice seeds. Int. J. Mol. Sci. 2013;14:3556-3567.

    Not in our library10.3390/ijms14023556

  111. 111.

    Guan C., Du X., Wang G., Ji J., Jin C., Li X. Expression of biologically active anti-thrombosis protein lumbrokinase in edible sunflower seed kernel. J. Plant Biochem. Biotechnol. 2014;23:257-265.

    Not in our library10.1007/s13562-013-0209-7

  112. 112.

    Tan Y., Wang K.Y., Wang N., Li G., Liu D. Ectopic expression of human acidic fibroblast growth factor 1 in the medicinal plant, Salvia miltiorrhiza, accelerates the healing of burn wounds. BMC Biotechnol. 2014;14:74.

    Not in our library10.1186/1472-6750-14-74

  113. 113.

    Limkul J., Misaki R., Kato K., Fujiyama K. The combination of plant translational enhancers and terminator increase the expression of human glucocerebrosidase in Nicotiana benthamiana plants. Plant Sci. 2015;240:41-49.

    Not in our library10.1016/j.plantsci.2015.08.018

  114. 114.

    Su J., Sherman A., Doerfler P.A., Byrne B.J., Herzog R.W., Daniell H. Oral delivery of Acid Alpha Glucosidase epitopes expressed in plant chloroplasts suppresses antibody formation in treatment of Pompe mice. Plant Biotechnol. J. 2015;13:1023-1032.

    Not in our library10.1111/pbi.12413

  115. 115.

    Wang Y.P., Wei Z.Y., Zhong X.F., Lin C.J., Cai Y.H., Ma J., Zhang Y.Y., Liu Y.Z., Xing S.C. Stable expression of basic fibroblast growth factor in chloroplasts of tobacco. Int. J. Mol. Sci. 2016;17:19.

    Not in our library10.3390/ijms17010019

  116. 116.

    Castiglia D., Sannino L., Marcolongo L., Ionata E., Tamburino R., De Stradis A., Cobucci-Ponzano B., Moracci M., La Cara F., Scotti N. High-level expression of thermostable cellulolytic enzymes in tobacco transplastomic plants and their use in hydrolysis of an industrially pretreated Arundo donax L. biomass. Biotechnol. Biofuels. 2016;9:154.

    Not in our library10.1186/s13068-016-0569-z

  117. 117.

    Rattanapisit K., Abdulheem S., Chaikeawkaew D., Kubera A., Mason H.S., Ma J.K., Pavasant P., Phoolcharoen W. Recombinant human osteopontin expressed in Nicotiana benthamiana stimulates osteogenesis related genes in human periodontal ligament cells. Sci. Rep. 2017;7:17358.

    Not in our library10.1038/s41598-017-17666-7

  118. 118.

    Ahmad A.R., Kaewpungsup P., Khorattanakulchai N., Rattanapisit K., Pavasant P., Phoolcharoen W. Recombinant human dentin matrix protein 1 (hDMP1) expressed in Nicotiana benthamiana potentially induces osteogenic differentiation. Plants. 2019;8:566.

    Not in our library10.3390/plants8120566

  119. 119.

    Menary J., Hobbs M., Mesquita de Albuquerque S., Pacho A., Drake P.M.W., Prendiville A., Ma J.K., Fuller S.S. Shotguns vs Lasers: Identifying barriers and facilitators to scaling-up plant molecular farming for high-value health products. PLoS ONE. 2020;15:e0229952.

    Not in our library10.1371/journal.pone.0229952

  120. 120.

    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.

    Not in our library10.1016/j.tibtech.2003.10.002

  121. 121.

    Yusibov V., Rabindran S. Recent progress in the development of plant derived vaccines. Expert Rev. Vaccines. 2008;7:1173-1183.

    Not in our library10.1586/14760584.7.8.1173

  122. 122.

    Gleba Y., Klimyuk V., Marillonnet S. Viral vectors for the expression of proteins in plants. Curr. Opin. Biotechnol. 2007;18:134-141.

    Not in our library10.1016/j.copbio.2007.03.002

  123. 123.

    Qiu X., Wong G., Audet J., Bello A., Fernando L., Alimonti J.B., Fausther-Bovendo H., Wei H., Aviles J., Hiatt E., et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014;514:47-53.

    Not in our library10.1038/nature13777

  124. 124.

    Rosales-Mendoza S. Will plant-made biopharmaceuticals play a role in the fight against COVID-19? Expert Opin. Biol. Ther. 2020;20:545-548.

    Not in our library10.1080/14712598.2020.1752177

  125. 125.

    Shanmugaraj B., Siriwattananon K., Wangkanont K., Phoolcharoen W. Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac. J. Allergy Immunol. 2020;38:10-18.

    Not in our library10.12932/ap-200220-0773

  126. 126.

    Capell T., Twyman R.M., Armario-Najera V., Ma J.K.C., Schillberg S., Christou P. Potential applications of plant biotechnology against SARS-CoV-2. Trends Plant Sci. 2020;25:635-643.

    Not in our library10.1016/j.tplants.2020.04.009

  127. 127.

    Buyel J.F. Plant molecular farming—Integration and exploitation of side streams to achieve sustainable biomanufacturing. Front. Plant Sci. 2018;9:1893.

    Not in our library10.3389/fpls.2018.01893

  128. 128.

    Maliga P. Engineering the plastid genome of higher plants. Curr. Opin. Plant Biol. 2002;5:164-172.

    Not in our library10.1016/s1369-5266(02)00248-0

  129. 129.

    Bock R. Plastid biotechnology: Prospects for herbicide and insect resistance, metabolic engineering and molecular farming. Curr. Opin. Biotechnol. 2007;18:100-106.

    Not in our library10.1016/j.copbio.2006.12.001

  130. 130.

    Jin S., Daniell H. The engineered chloroplast genome just got smarter. Trends Plant Sci. 2015;20:622-640.

    Not in our library10.1016/j.tplants.2015.07.004

  131. 131.

    Zhang B., Shanmugaraj B., Daniell H. Expression and functional evaluation of biopharmaceuticals made in plant chloroplasts. Curr. Opin. Chem. Biol. 2017;38:17-23.

    Not in our library10.1016/j.cbpa.2017.02.007

  132. 132.

    Xu J., Zhang N. On the way to commercializing plant cell culture platform for biopharmaceuticals: Present status and prospect. Pharm. Bioprocess. 2014;2:499-518.

    Not in our library10.4155/pbp.14.32

  133. 133.

    Tekoah Y., Shulman A., Kizhner T., Ruderfer I., Fux L., Nataf Y., Bartfeld D., Ariel T., Gingis–Velitski S., Hanania U., et al. Large-scale production of pharmaceutical proteins in plant cell culture—The protalix experience. Plant Biotechnol. J. 2015;13:1199-1208.

    Not in our library10.1111/pbi.12428

  134. 134.
    Putting the Spotlight Back on Plant Suspension Cultures · 2016
    No notice
  135. 135.
    Biologically active recombinant human erythropoietin expressed in hairy root cultures and regenerated plantlets of Nicotiana tabacum L. · 2017
    Not checked
  136. 136.
    Hairy Root Cultures—A Versatile Tool With Multiple Applications · 2020
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