Plant-made pharmaceuticals: exploring studies for the production of recombinant protein in plants and assessing challenges ahead

Aguirreburualde MSP, Gómez MC, Ostachuk A, Wolman F, Albanesi G, Pecora A, Odeon A, Ardila F, Escribano JM, Santos MJD (2013) Efficacy of a BVDV subunit vaccine produced in alfalfa transgenic plants. Vet Immunol Immunopathol 151(3–4):315–324. https://doi.org/10.1016/j.vetimm.2012.12.004 Altpeter F, Baisakh N, Beachy R, Bock R, Capell T, Christou P, Daniell H, Datta K, Datta S, Dix PJ, Fauquet C, Huang N, Kohli A, Mooibroek H, Nicholson L, Nguyen TT, Nugent G, Raemakers K, Romano A, Somers DA, Stoger E, Taylor N, Visser R (2005) Particle bombardment and the genetic enhancement of crops: myths and realities. Mol Breed 15:305–327. https://doi.org/10.1007/s11032-004-8001-y Anderson AR, Moore LW (1979) Host specificity in the genus Agrobacterium. Phytopathol 69(4):320-323 Arai K-i, Lee F, Miyajima A, Miyatake S, Arai N, Yokota T (1990) Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem 59(1):783–836. https://doi.org/10.1146/annurev.bi.59.070190.004031 Balke I, Zeltins A (2019) Use of plant viruses and virus-like particles for the creation of novel vaccines. Adv Drug Del Rev 145:119–129. https://doi.org/10.1016/j.addr.2018.08.007 Birch RG (1997) Plant tramsformation: problems and strategies for practical application. Annu Rev Plant Biol 48(1):297–326. https://doi.org/10.1146/annurev.arplant.48.1.297 Bosch D, Castilho A, Loos A, Schots A, Steinkellner H (2013) N-glycosylation of plant-produced recombinant proteins. Curr Pharm Des 19(31):5503–5512. https://doi.org/10.2174/138161281139310006 Bosma T, Kanninga R, Neef J, Audouy SA, van Roosmalen ML, Steen A, Buist G, Kok J, Kuipers OP, Robillard G (2006) Novel surface display system for proteins on non-genetically modified gram-positive bacteria. Appl Environ Microbiol 72(1):880–889. https://doi.org/10.1128/AEM.72.1.880-889.2006 Buist G, Steen A, Kok J, Kuipers OP (2008) LysM, a widely distributed protein motif for binding to (peptido) glycans. Mol Microbiol 68(4):838–847. https://doi.org/10.1111/j.1365-2958.2008.06211.x Butler M (2003) Animal cell culture and technology. Taylor & Francis, pp 1–29. https://doi.org/10.4324/9780203427835 Çelik E, Çalık P (2012) Production of recombinant proteins by yeast cells. Biotechnol Adv 30(5):1108–1118. https://doi.org/10.1016/j.biotechadv.2011.09.011 Choi BK, Bobrowicz P, Davidson RC, Hamilton SR, Kung DH, Li H, Miele RG, Nett JH, Wildt S, Gerngross TU (2003) Use of combinatorial genetic libraries to humanize N-linked glycosylation in the yeast Pichia pastoris. Proc Natl Acad Sci USA 100(9):5022–5027. https://doi.org/10.1073/pnas.0931263100 Christou P (1996) Transformation technology. Trends Plant Sci 1(12):423–431. https://doi.org/10.1016/S1360-1385(96)10047-9 Conley AJ, Zhu H, Le LC, Jevnikar AM, Lee BH, Brandle JE, Menassa R (2011) Recombinant protein production in a variety of Nicotiana hosts: a comparative analysis. Plant Biotechnol J 9(4):434–444. https://doi.org/10.1111/j.1467-7652.2010.00563.x Cunha N, Araújo A, Leite A, Murad A, Vianna G, Rech E (2010) Correct targeting of proinsulin in protein storage vacuoles of transgenic soybean seeds. Genet Mol Res 9(2):1163–1170. https://doi.org/10.4238/vol9-2gmr849 D’Aoust MA, Lavoie PO, Couture MMJ, Trépanier S, Guay JM, Dargis M, Mongrand S, Landry N, Ward BJ, Vézina LP (2008) 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 6(9):930–940. https://doi.org/10.1111/j.1467-7652.2008.00384.x Dan Y (2008) Biological functions of antioxidants in plant transformation. In Vitro Cell Dev Biol - Plant 44(3):149–161. https://doi.org/10.1007/s11627-008-9110-9 Daniell H, Vivekananda J, Nielsen BL, Ye GN, Tewari KK, Sanford JC (1990) Transient foreign gene expression in chloroplasts of cultured tobacco cells after biolistic delivery of chloroplast vectors. Proc Natl Acad Sci USA 87(1):88–92. https://doi.org/10.1073/pnas.87.1.88 Daniell H, Khan MS, Allison L (2002) Milestones in chloroplast genetic engineering: an environmentally friendly era in biotechnology. Trends Plant Sci 7(2):84–91. https://doi.org/10.1016/S1360-1385(01)02193-8 Daniell H, Kumar S, Dufourmantel N (2005) Breakthrough in chloroplast genetic engineering of agronomically important crops. Trends Biotechnol 23(5):238–245. https://doi.org/10.1016/j.tibtech.2005.03.008 D’Aoust M-A, Busse U, Martel M, Lerouge P, Levesque D, Vézina L-P (2004) Perennial plants as a production system for pharmaceuticals. Handb Plant Biotechnol. https://doi.org/10.1002/0470869143.kc043 De La Riva GA, González-Cabrera J, Vázquez-Padrón R, Ayra-Pardo C (1998) Agrobacterium tumefaciens: a natural tool for plant transformation. Electron J Biotechnol 1(3):24–25. https://doi.org/10.4067/S0717-34581998000300002 Demain AL, Vaishnav P (2009) Production of recombinant proteins by microbes and higher organisms. Biotechnol Adv 27(3):297–306. https://doi.org/10.1016/j.biotechadv.2009.01.008 Dent M, Hurtado J, Paul AM, Sun H, Lai H, Yang M, Esqueda A, Bai F, Steinkellner H, Chen Q (2016) Plant-produced anti-dengue virus monoclonal antibodies exhibit reduced antibody-dependent enhancement of infection activity. J Gen Virol 97(12):3280–3290. https://doi.org/10.1099/jgv.0.000635 Diamos AG, Hunter JGL, Pardhe MD, Rosenthal SH, Sun H, Foster BC, DiPalma MP, Chen Q, Mason HS (2020) High level production of monoclonal antibodies using an optimized plant expression system. Front Bioeng Biotechnol. https://doi.org/10.3389/fbioe.2019.00472 Díaz AH, Koop H-U (2014) Nicotiana tabacum: PEG-mediated plastid transformation. In: Maliga P (ed) Chloroplast biotechnology: methods and protocols. Humana Press, Totowa, pp 165–175. https://doi.org/10.1007/978-1-62703-995-6_9 Ding S-H, Huang L-Y, Wang Y-D, Sun H-C, Xiang Z-H (2006) High-level expression of basic fibroblast growth factor in transgenic soybean seeds and characterization of its biological activity. Biotechnol Lett 28(12):869–875. https://doi.org/10.1007/s10529-006-9018-6 Ellis RW (1999) New technologies for making vaccines. Vaccine 17(13–14):1596–1604. https://doi.org/10.1016/S0264-410X(98)00416-2 Escobar CM, Escobar AC (2017) Duckweed: a tiny aquatic plant with enormous potential for bioregenerative life support systems. Int Conf Environ Syst 281:1-9 Fernandes F, Vidigal J, Dias MM, Prather KLJ, Coroadinha AS, Teixeira AP, Alves PM (2012) Flipase-mediated cassette exchange in Sf9 insect cells for stable gene expression. Biotechnol Bioeng 109(11):2836–2844. https://doi.org/10.1002/bit.24542 Ferrer-Miralles N, Domingo-Espín J, Corchero JL, Vázquez E, Villaverde A (2009) Microbial factories for recombinant pharmaceuticals. Microb Cell Factor 8(1):1–8. https://doi.org/10.1186/1475-2859-8-17 Firsov A, Tarasenko I, Mitiouchkina T, Ismailova N, Shaloiko L, Vainstein A, Dolgov S (2015) High-yield expression of M2e peptide of avian influenza virus H5N1 in transgenic duckweed plants. Mol Biotechnol 57(7):653–661. https://doi.org/10.1007/s12033-015-9855-4 Fischer R, Drossard J, Commandeur U, Schillberg S, Emans N (1999a) Towards molecular farming in the future: moving from diagnostic protein and antibody production in microbes to plants. Biotechnol Appl Biochem 30(2):101–108. https://doi.org/10.1111/j.1470-8744.1999.tb00898.x Fischer R, Liao Y-C, Hoffmann K, Schillberg S, Emans N (1999b) Molecular farming of recombinant antibodies in plants. Biol Chem 380(7–8):825–839. https://doi.org/10.1515/BC.1999.102 Fischer R, Stoger E, Schillberg S, Christou P, Twyman RM (2004) Plant-based production of biopharmaceuticals. Curr Opin Plant Biol 7(2):152–158. https://doi.org/10.1016/j.pbi.2004.01.007 Floss DM, Sack M, Stadlmann J, Rademacher T, Scheller J, Stöger E, Fischer R, Conrad U (2008) Biochemical and functional characterization of anti-HIV antibody–ELP fusion proteins from transgenic plants. Plant Biotechnol J 6(4):379–391. https://doi.org/10.1111/j.1467-7652.2008.00326.x Fox JL (2012) First plant-made biologic approved. Nat Biotechnol 30(6):472–473. https://doi.org/10.1038/nbt0612-472 Ganapathi T, Kumar GS, Srinivas L, Revathi C, Bapat V (2007) Analysis of the limitations of hepatitis B surface antigen expression in soybean cell suspension cultures. Plant Cell Rep 26(9):1575–1584. https://doi.org/10.1007/s00299-007-0379-7 Gellison G, Janowicz ZA, Weydemann U, Melber K, Strasser AWM, Hollenberg CP (1992) High-level expression of foreign genes in Hansenula polymorpha. Biotech Adv 10:179–189. https://doi.org/10.1016/0734-9750(92)90002-Q Gelvin SB (2003) Agrobacterium-mediated plant transformation: the biology behind the “gene-jockeying” tool. Microbiol Mol Rev 67(1):16–37. https://doi.org/10.1128/MMBR.67.1.16-37.2003 Giddings G (2001) Transgenic plants as protein factories. Curr Opin Biotechnol 12:450–454. https://doi.org/10.1016/s0958-1669(00)00244-5 Goeddel DV, Kleid DG, Bolivar F, Heyneker HL, Yansura DG, Crea R, Hirose T, Kraszewski A, Itakura K, Riggs AD (1979) Expression in Escherichia coli of chemically synthesized genes for human insulin. Proc Natl Acad Sci USA 76(1):106–110. https://doi.org/10.1073/pnas.76.1.106 Guerrero-Andrade O, Loza-Rubio E, Olivera-Flores T, Fehérvári-Bone T, Gómez-Lim MA (2006) Expression of the Newcastle disease virus fusion protein in transgenic maize and immunological studies. Transgenic Res 15(4):455–463. https://doi.org/10.1007/s11248-006-0017-0 Gunter CJ, Regnard GL, Rybicki EP, Hitzeroth II (2019) Immunogenicity of plant-produced porcine circovirus-like particles in mice. Plant Biotechnol J 17(9):1751–1759. https://doi.org/10.1111/pbi.13097 Hayashimoto A, Li Z, Murai N (1990) A polyethylene glycol-mediated protoplast transformation system for production of fertile transgenic rice plants. Plant Physiol 93(3):857–863. https://doi.org/10.1104/pp.93.3.857 He Y, Ning T, Xie T, Qiu Q, Zhang L, Sun Y, Jiang D, Fu K, Yin F, Zhang W, Shen L, Wang H, Li J, Lin Q, Sun Y, Li H, Zhu Y, Yang D (2011) Large-scale production of functional human serum albumin from transgenic rice seeds. Proc Natl Acad Sci USA 108(47):19078–19083. https://doi.org/10.1073/pnas.1109736108 Hellwig S, Drossard J, Twyman RM, Fischer R (2004) Plant cell cultures for the production of recombinant proteins. Nat Biotechnol 22(11):1415–1422. https://doi.org/10.1038/nbt1027 Hiatt A, Caffferkey R, Bowdish K (1989) Production of antibodies in transgenic plants. Nature 342(6245):76–78. https://doi.org/10.1038/342076a0 Hoekema A, Hirsch PR, Hooykaas PJJ, Schilperoort RA (1983) A binary plant vector strategy based on separation of vir- and T-region of the Agrobacterium tumefaciens Ti-plasmid. Nature 303(5913):179–180. https://doi.org/10.1038/303179a0 Holland T, Sack M, Rademacher T, Schmale K, Altmann F, Stadlmann J, Fischer R, Hellwig S (2010) Optimal nitrogen supply as a key to increased and sustained production of a monoclonal full-size antibody in BY-2 suspension culture. Biotechnol Bioeng 107(2):278–289. https://doi.org/10.1002/bit.22800 Holtz BR, Berquist BR, Bennett LD, Kommineni VJM, Munigunti RK, White EL, Wilkerson DC, Wong K-YI, Ly LH, Marcel S (2015) Commercial-scale biotherapeutics manufacturing facility for plant-made pharmaceuticals. Plant Biotechnol J 13(8):1180–1190. https://doi.org/10.1111/pbi.12469 Horsch RB, Fry JE, Hoffmann NL, Wallroth M, Eichholtz D, Rogers SG, Fraley RT (1985) A simple and general method for transferring genes into plants. Science 227(4691):1229–1231. https://doi.org/10.1126/science.227.4691.1229 Huang Z, LePore K, Elkin G, Thanavala Y, Mason HS (2008) High-yield rapid production of hepatitis B surface antigen in plant leaf by a viral expression system. Plant Biotechnol J 6(2):202–209. https://doi.org/10.1111/j.1467-7652.2007.00316.x Hudson LC, Bost KL, Piller KJ (2011) Optimizing recombinant protein expression in soybean. In: Soybean-molecular aspects of breeding InTech Open, pp 19–42 Jansing J, Sack M, Augustine SM, Fischer R, Bortesi L (2019) CRISPR/Cas9-mediated knockout of six glycosyltransferase genes in Nicotiana benthamiana for the production of recombinant proteins lacking β-1,2-xylose and core α-1,3-fucose. Plant Biotechnol J 17(2):350–361. https://doi.org/10.1111/pbi.12981 Jiang MC, Hu CC, Lin NS, Hsu YH (2019) Production of human IFNγ protein in Nicotiana benthamiana plant through an enhanced expression system based on bamboo mosaic virus. Viruses. https://doi.org/10.3390/v11060509 Joensuu J, Verdonck F, Ehrström A, Peltola M, Siljander-Rasi H, Nuutila A-M, Oksman-Caldentey K-M, Teeri T, Cox E, Goddeeris B (2006) F4 (K88) fimbrial adhesin FaeG expressed in alfalfa reduces F4+ enterotoxigenic Escherichia coli excretion in weaned piglets. Vaccine 24(13):2387–2394. https://doi.org/10.1016/j.vaccine.2005.11.056 Kalthoff D, Giritch A, Geisler K, Bettmann U, Klimyuk V, Hehnen H-R, Gleba Y, Beer M (2010) Immunization with plant-expressed hemagglutinin protects chickens from lethal highly pathogenic avian influenza virus H5N1 challenge infection. J Virol 84(22):12002–12010. https://doi.org/10.1128/JVI.00940-10 Kanagarajan S, Tolf C, Lundgren A, Waldenström J, Brodelius PE (2012) Transient expression of hemagglutinin antigen from low pathogenic avian influenza A (H7N7) in Nicotiana benthamiana. PLoS ONE 7(3):e33010. https://doi.org/10.1371/journal.pone.0033010 Kapila J, De Rycke R, Van Montagu M, Angenon G (1997) An Agrobacterium-mediated transient gene expression system for intact leaves. Plant Sci 122(1):101–108. https://doi.org/10.1016/S0168-9452(96)04541-4 Kay R, Chan A, Daly M, McPherson J (1987) Duplication of CaMV 35S promoter sequences creates a strong enhancer for plant genes. Science 236(4806):1299–1302. https://doi.org/10.1126/science.236.4806.1299 Komori T, Imayama T, Kato N, Ishida Y, Ueki J, Komari T (2007) Current status of binary vectors and superbinary vectors. Plant Physiol 145(4):1155–1160. https://doi.org/10.1104/pp.107.105734 Koprivova A, Stemmer C, Altmann F, Hoffmann A, Kopriva S, Gorr G, Reski R, Decker EL (2004) Targeted knockouts of Physcomitrella lacking plant-specific immunogenic N-glycans. Plant Biotechnol J 2(6):517–523. https://doi.org/10.1111/j.1467-7652.2004.00100.x Kumar GB, Ganapathi TR, Revathi CJ, Srinivas L, Bapat VA (2005) Expression of hepatitis B surface antigen in transgenic banana plants. Planta 222(3):484–493. https://doi.org/10.1007/s00425-005-1556-y Kushnir N, Streatfield SJ, Yusibov V (2012) Virus-like particles as a highly efficient vaccine platform: Diversity of targets and production systems and advances in clinical development. Vaccine 31(1):58–83. https://doi.org/10.1016/j.vaccine.2012.10.083 Kuta DD, Tripathi L (2005) Agrobacterium-induced hypersensitive necrotic reaction in plant cells: a resistance response against Agrobacterium-mediated DNA transfer. Afr J Biotechnol 4(8):752–757. https://doi.org/10.5897/AJB2005.000-3149 Kwon T-H, Kim Y-S, Lee J-H, Yang M-S (2003) Production and secretion of biologically active human granulocyte-macrophage colony stimulating factor in transgenic tomato suspension cultures. Biotechnol Lett 25(18):1571–1574. https://doi.org/10.1023/a:1025409927790 Kwon K-C, Chan H-T, León IR, Williams-Carrier R, Barkan A, Daniell H (2016) Codon optimization to enhance expression yields insights into chloroplast translation. Plant Physiol 172(1):62–77. https://doi.org/10.1104/pp.16.00981 Kwon KC, Sherman A, Chang WJ, Kamesh A, Biswas M, Herzog RW, Daniell H (2018) Expression and assembly of largest foreign protein in chloroplasts: oral delivery of human FVIII made in lettuce chloroplasts robustly suppresses inhibitor formation in haemophilia A mice. Plant Biotechnol J 16(6):1148–1160. https://doi.org/10.1111/pbi.12859 Laguia-Becher M, Zaldúa Z, Xu W, Marconi PL, Velander W, Alvarez MA (2019) Co-expressing Turnip Crinkle Virus-coat protein with the serine protease α-thrombin precursor (pFIIa) in Nicotiana benthamiana Domin. In Vitro Cell Dev Biol Plant 55(1):88–98 Landolt E, Kandeler R (1987) Biosystematic investigations in the family of duckweeds (Lemnaceae), Vol. 4: the family of Lemnaceae-a monographic study, Vol. 2 (phytochemistry, physiology, application, bibliography). Veroeffentlichungen des Geobotanischen Instituts der ETH, Stiftung Ruebel Lau OS, Sun SSM (2009) Plant seeds as bioreactors for recombinant protein production. Biotechnol Adv 27(6):1015–1022. https://doi.org/10.1016/j.biotechadv.2009.05.005 Lee MW, Yang Y (2006) Transient expression assay by agroinfiltration of leaves. Methods Mol Biol 323:225–229. https://doi.org/10.1385/1-59745-003-0:225 Lico C, Chen Q, Santi L (2008) Viral vectors for production of recombinant proteins in plants. J Cell Physiol 216(2):366–377. https://doi.org/10.1002/jcp.21423 Liles WC, Van Voorhis WC (1995) Nomenclature and biologic significance of cytokines involved in inflammation and the host immune response. J Infect Dis 172(6):1573–1580. https://doi.org/10.1093/infdis/172.6.1573 Ma JKC, Drake PMW, Christou P (2003) The production of recombinant pharmaceutical proteins in plants. Nat Rev Genet 4(10):794–805. https://doi.org/10.1038/nrg1177 Maharjan PM, Cheon J, Jung J, Kim H, Lee J, Song M, Jeong GU, Kwon Y, Shim B, Choe S (2021) Plant-expressed receptor binding domain of the SARS-CoV-2 spike protein elicits humoral immunity in mice. Vaccines 9(9):978. https://doi.org/10.3390/vaccines9090978 Mannucci PM, Tuddenham EG (2001) The hemophilias–from royal genes to gene therapy. N Engl J Med 344(23):1773–1779. https://doi.org/10.1056/nejm200106073442307 Margolin E, Chapman R, Williamson AL, Rybicki EP, Meyers AE (2018) Production of complex viral glycoproteins in plants as vaccine immunogens. Plant Biotechnol J 16(9):1531–1545. https://doi.org/10.1111/pbi.12963 Marillonnet S, Giritch A, Gils M, Kandzia R, Klimyuk V, Gleba Y (2004) In planta engineering of viral RNA replicons: efficient assembly by recombination of DNA modules delivered by Agrobacterium. Proc Natl Acad Sci USA 101(18):6852. https://doi.org/10.1073/pnas.0400149101 Marsian J, Fox H, Bahar MW, Kotecha A, Fry EE, Stuart DI, Macadam AJ, Rowlands DJ, Lomonossoff GP (2017) Plant-made polio type 3 stabilized VLPs—a candidate synthetic polio vaccine. Nat Commun 8(1):1–9. https://doi.org/10.1038/s41467-017-00090-w Martin W, Rujan T, Richly E, Hansen A, Cornelsen S, Lins T, Leister D, Stoebe B, Hasegawa M, Penny D (2002) Evolutionary analysis of Arabidopsis, cyanobacterial, and chloroplast genomes reveals plastid phylogeny and thousands of cyanobacterial genes in the nucleus. Proc Natl Acad Sci USA 99(19):12246–12251. https://doi.org/10.1073/pnas.182432999 Mbewana S, Mortimer E, Pêra FF, Hitzeroth II, Rybicki EP (2015) 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 3:197. https://doi.org/10.3389/fbioe.2015.00197 Meinke DW, Cherry JM, Dean C, Rounsley SD, Koornneef M (1998) Arabidopsis thaliana: a model plant for genome analysis. Science 282(5389):662–682. https://doi.org/10.1126/science.282.5389.662 Meyer H, Brass J, Jungo C, Klein J, Wenger J, Mommers R (2008) An emerging star for therapeutic and catalytic protein production. Bioprocess Int 6:10 Mikschofsky H, Hammer M, Schmidtke J, König P, Keil G, Schirrmeier H, Schmidt K, Broer I (2009) Optimization of growth performance of freshly induced carrot suspensions concerning PMP production. In Vitro Cell Dev Biol Plant 45(6):740–749. https://doi.org/10.1007/s11627-008-9189-z Murray K (1988) Application of recombinant DNA techniques in the development of viral vaccines. Vaccine 6(2):164–174. https://doi.org/10.1016/s0264-410x(88)80022-7 Noad R, Roy P (2003) Virus-like particles as immunogens. Trends Microbiol 11(9):438–444. https://doi.org/10.1016/S0966-842X(03)00208-7 Nosaki S, Hoshikawa K, Ezura H, Miura K (2021) Transient protein expression systems in plants and their applications. Plant Biotechnol (tokyo) 38(3):297–304. https://doi.org/10.5511/plantbiotechnology.21.0610a O’Flaherty R, Bergin A, Flampouri E, Mota LM, Obaidi I, Quigley A, Xie Y, Butler M (2020) Mammalian cell culture for production of recombinant proteins: a review of the critical steps in their biomanufacturing. Biotechnol Adv 43:107552. https://doi.org/10.1016/j.biotechadv.2020.107552 O’Neill C, Horvath GV, Horvath E, Dix PJ, Medgyesy P (1993) Chloroplast transformation in plants: polyethylene glycol (PEG) treatment of protoplasts is an alternative to biolistic delivery systems. Plant J 3(5):729–738. https://doi.org/10.1111/j.1365-313X.1993.00729.x Otto R, Santagostino A, Schrader U (2014) Rapid growth in biopharma: challenges and opportunities. McKinsey & Company Özyiğit İİ (2012) Agrobacterium tumefaciens and its use in plant biotechnology. In: Ashraf M, Öztürk M, Ahmad MSA, Aksoy A (eds) Crop production for agricultural improvement. Springer Netherlands, Dordrecht, pp 317–361. https://doi.org/10.1007/978-94-007-4116-4_12 Park SH, Ji K-Y, Park SY, Kim HM, Ma SH, Do JH, Kang H, Kang HS, Oh D-B, Shim JS (2022) Immunotherapeutic effects of recombinant colorectal cancer antigen produced in tomato fruits. Sci Rep 12(1):1–10. https://doi.org/10.1038/s41598-022-13839-1 Parsons J, Altmann F, Graf M, Stadlmann J, Reski R, Decker EL (2013) A gene responsible for prolyl-hydroxylation of moss-produced recombinant human erythropoietin. Sci Rep 3(1):1–8. https://doi.org/10.1038/srep03019 Paul M, Ma JKC (2011) Plant-made pharmaceuticals: leading products and production platforms. Biotechnol Appl Biochem 58:58–67. https://doi.org/10.1002/bab.6 Pettitt J, Zeitlin L, Kim DH, Working C, Johnson JC, Bohorov O, Bratcher B, Hiatt E, Hume SD, Johnson AK, Morton J, Pauly MH, Whaley KJ, Ingram MF, Zovanyi A, Heinrich M, Piper A, Zelko J, Olinger GG (2013) Therapeutic intervention of ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail. Sci Transl Med 5(199):199ra113. https://doi.org/10.1126/scitranslmed.3006608 Pires AS, Rosa S, Castanheira S, Fevereiro P, Abranches R (2012) Expression of a recombinant human erythropoietin in suspension cell cultures of Arabidopsis, tobacco and Medicago. Plant Cell Tissue Organ Cult 110(1):171–181. https://doi.org/10.1007/s11240-012-0141-x Plasson C, Michel R, Lienard D, Saint-Jore-Dupas C, Sourrouille C, de March GG, Gomord V (2009) Production of recombinant proteins in suspension–cultured plant cells. Methods Mol Biol 483:145-161 https://doi.org/10.1007/978-1-59745-407-0_9 Popov SV, Golovchenko VV, Ovodova RG, Smirnov VV, Khramova DS, Popova GY, Ovodov YS (2006) Characterisation of the oral adjuvant effect of lemnan, a pectic polysaccharide of Lemna minor L. Vaccine 24(26):5413–5419. https://doi.org/10.1016/j.vaccine.2006.03.076 Potrykus I (1991) Gene transfer to plants: assessment of published approaches and results. Annu Rev Plant Physiol 42(1):205–225 Pumpens P, Grens E (2002) Artificial genes for chimeric virus-like particles. Artif DNA Methods Appl 249:327 Rattanapisit K, Phakham T, Buranapraditkun S, Siriwattananon K, Boonkrai C, Pisitkun T, Hirankarn N, Strasser R, Abe Y, Phoolcharoen W (2019) Structural and in vitro functional analyses of novel plant-produced anti-human PD1 antibody. Sci Rep 9(1):1–10. https://doi.org/10.1038/s41598-019-51656-1 Redwan E-RM (2007) Cumulative updating of approved biopharmaceuticals. Hum Antib 16(3–4):137–158 Renuga G, Saravanan R, Thandapani AB, Arumugam K (2010) Expression of cholera toxin B subunit in Banana callus culture. J Pharm Sci & Res 2(1):26 Reski R, Cove DJ (2004) Physcomitrella patens. Curr Biol 14(7):R261–R262 Rival S, Wisniewski J-P, Langlais A, Kaplan H, Freyssinet G, Vancanneyt G, Vunsh R, Perl A, Edelman M (2008) Spirodela (duckweed) as an alternative production system for pharmaceuticals: a case study, aprotinin. Transgenic Res 17(4):503–513. https://doi.org/10.1007/s11248-007-9123-x Rosales-Mendoza S, Tello-Olea MA (2015) Carrot cells: a pioneering platform for biopharmaceuticals production. Mol Biotechnol 57(3):219–232. https://doi.org/10.1007/s12033-011-9837-y Sainsbury F, Lomonossoff GP (2008) Extremely high-level and rapid transient protein production in plants without the use of viral replication. Plant Physiol 148(3):1212–1218. https://doi.org/10.1104/pp.108.126284 Schachtsiek J, Stehle F (2019) Nicotine-free, nontransgenic tobacco (Nicotiana tabacum l.) edited by CRISPR-Cas9. Plant Biotechnol J 17(12):2228–2230. https://doi.org/10.1111/pbi.13193 Schillberg S, Emans N, Fischer R (2002) Antibody molecular farming in plants and plant cells. Phytochem Rev 1(1):45–54. https://doi.org/10.1023/A:1015880218651 Schillberg S, Raven N, Fischer R, Twyman MR, Schiermeyer A (2013) Molecular farming of pharmaceutical proteins using plant suspension cell and tissue cultures. Curr Pharm Des 19(31):5531–5542. https://doi.org/10.2174/1381612811319310008 Schillberg S, Raven N, Spiegel H, Rasche S, Buntru M (2019) Critical Analysis of the Commercial Potential of Plants for the Production of Recombinant Proteins. Front Plant Sci. https://doi.org/10.3389/fpls.2019.00720 Scholthof HB, Scholthof KBG, Jackson AO (1996) Plant virus gene vectors for transient expression of foreign proteins in plants. Annu Rev Phytopathol 34(1):299–323. https://doi.org/10.1146/annurev.phyto.34.1.299 Sedaghati B, Haddad R, Bandehpour M (2020) Transient expression of human serum albumin (HSA) in tobacco leaves. Mol Biol Rep 47(9):7169–7177. https://doi.org/10.1007/s11033-020-05640-y Shanmugaraj B, Christine JIB, Phoolcharoen W (2020) Plant molecular farming: a viable platform for recombinant biopharmaceutical production. Plants 9(7):842. https://doi.org/10.3390/plants9070842 Sherman A, Su J, Lin S, Wang X, Herzog RW, Daniell H (2014) Suppression of inhibitor formation against FVIII in a murine model of hemophilia A by oral delivery of antigens bioencapsulated in plant cells. Blood 124(10):1659–1668. https://doi.org/10.1182/blood-2013-10-528737 Shim BS, Hong KJ, Maharjan PM, Choe S (2019) Plant factory: new resource for the productivity and diversity of human and veterinary vaccines. Clin Exp Vaccine Res 8:136–139. https://doi.org/10.7774/cevr.2019.8.2.136 Shoji Y, Farrance CE, Bautista J, Bi H, Musiychuk K, Horsey A, Park H, Jaje J, Green BJ, Shamloul M (2012) A plant-based system for rapid production of influenza vaccine antigens. Influenza Other Respir Viruses 6(3):204–210. https://doi.org/10.1111/j.1750-2659.2011.00295.x Simmons CW, VanderGheynst JS, Upadhyaya SK (2009) A model of Agrobacterium tumefaciens vacuum infiltration into harvested leaf tissue and subsequent in planta transgene transient expression. Biotechnol Bioeng 102(3):965–970. https://doi.org/10.1002/bit.22118 Smith T, O’Kennedy MM, Wandrag DB, Adeyemi M, Abolnik C (2020) Efficacy of a plant-produced virus-like particle vaccine in chickens challenged with Influenza A H6N2 virus. Plant Biotechnol J 18(2):502–512. https://doi.org/10.1111/pbi.13219 So Y, Lee K-J, Kim D-S, Lee J-H, Oh D-B, Hwang K-A, Ko K, Choo Y-K, Ko K (2013) Glycomodification and characterization of anti-colorectal cancer immunotherapeutic monoclonal antibodies in transgenic tobacco. Plant Cell Tissue Organ Cult 113(1):41–49. https://doi.org/10.1007/s11240-012-0249-z Song S-J, Shin G-I, Noh J, Lee J, Kim D-H, Ryu G, Ahn G, Jeon H, Diao H-P, Park Y, Kim MG, Kim W-Y, Kim Y-J, Sohn E-J, Song CS, Hwang I (2021) Plant-based, adjuvant-free, potent multivalent vaccines for avian influenza virus via Lactococcus surface display. J Integr Plant Biol 63(8):1505–1520. https://doi.org/10.1111/jipb.13141 Stander J, Chabeda A, Rybicki EP, Meyers AE (2021) A plant-produced virus-like particle displaying envelope protein domain III Elicits an immune response against west nile virus in mice. Front Plant Sci. https://doi.org/10.3389/fpls.2021.738619 Stefanova G, Slavov S, Gecheff K, Vlahova M, Atanassov A (2013) Expression of recombinant human lactoferrin in transgenic alfalfa plants. Biol Plant 57(3):457–464 Stoger E, Ma JKC, Fischer R, Christou P (2005) Sowing the seeds of success: pharmaceutical proteins from plants. Curr Opin Biotechnol 16(2):167–173. https://doi.org/10.1016/j.copbio.2005.01.005 Strasser R, Altmann F, Mach L, Glössl J, Steinkellner H (2004) Generation of Arabidopsis thaliana plants with complex N-glycans lacking β1,2-linked xylose and core α1,3-linked fucose. FEBS Lett 561(1–3):132–136. https://doi.org/10.1016/S0014-5793(04)00150-4 Tabayashi N, Matsumura T (2014) Forefront study of plant biotechnology for practical use: development of oral drug for animal derived from transgenic strawberry. Soc Biotechnol J Japn 92:537–539 Tekoah Y, Shulman A, Kizhner T, Ruderfer I, Fux L, Nataf Y, Bartfeld D, Ariel T, Gingis-Velitski S, Hanania U (2015) Large-scale production of pharmaceutical proteins in plant cell culture—the protalix experience. Plant Biotechnol J 13(8):1199–1208. https://doi.org/10.1111/pbi.12428 Thanavala Y, Mahoney M, Pal S, Scott A, Richter L, Natarajan N, Goodwin P, Arntzen CJ, Mason HS (2005) Immunogenicity in humans of an edible vaccine for hepatitis B. Proc Natl Acad Sci USA 102(9):3378–3382. https://doi.org/10.1073/pnas.0409899102 Thomas B, Van Deynze A, Bradford K (2002) Production of therapeutic proteins in plants. UCANR Publications, Oakland, pp 1–12. https://doi.org/10.3733/ucanr.8078 Twyman RM, Stoger E, Schillberg S, Christou P, Fischer R (2003) Molecular farming in plants: host systems and expression technology. Trends Biotechnol 21(12):570–578. https://doi.org/10.1016/j.tibtech.2003.10.002 van Montagu M (2003) Jeff Schell (1935–2003): steering Agrobacterium-mediated plant gene engineering. Trends Plant Sci 8(8):353–354. https://doi.org/10.1016/S1360-1385(03)00160-2 van Roosmalen ML, Kanninga R, El Khattabi M, Neef J, Audouy S, Bosma T, Kuipers A, Post E, Steen A, Kok J (2006) Mucosal vaccine delivery of antigens tightly bound to an adjuvant particle made from food-grade bacteria. Methods 38(2):144–149. https://doi.org/10.1016/j.ymeth.2005.09.015 Verma D, Moghimi B, LoDuca PA, Singh HD, Hoffman BE, Herzog RW, Daniell H (2010) Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice. Proc Natl Acad Sci USA 107(15):7101–7106. https://doi.org/10.1073/pnas.0912181107 Vermij P, Waltz E (2006) USDA approves the first plant-based vaccine. Nat Biotechnol 24(3):234. https://doi.org/10.1038/nbt0306-233 von Stackelberg M, Rensing SA, Reski R (2006) Identification of genic moss SSR markers and a comparative analysis of twenty-four algal and plant gene indices reveal species-specific rather than group-specific characteristics of microsatellites. BMC Plant Biol 6(1):1–14. https://doi.org/10.1186/1471-2229-6-9 Vunsh R, Li J, Hanania U, Edelman M, Flaishman M, Perl A, Wisniewski J-P, Freyssinet G (2007) High expression of transgene protein in Spirodela. Plant Cell Rep 26(9):1511–1519. https://doi.org/10.1007/s00299-007-0361-4 Ward BJ, Gobeil P, Séguin A, Atkins J, Boulay I, Charbonneau P-Y, Couture M, D’Aoust M-A, Dhaliwall J, Finkle C, Hager K, Mahmood A, Makarkov A, Cheng MP, Pillet S, Schimke P, St-Martin S, Trépanier S, Landry N (2021) Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19. Nat Med 27(6):1071–1078. https://doi.org/10.1038/s41591-021-01370-1 Winicur ZM, Feng Zhang G, Andrew Staehelin L (1998) Auxin deprivation induces synchronous Golgi differentiation in suspension-cultured tobacco BY-2 cells. Plant Physiol 117(2):501–513. https://doi.org/10.1104/pp.117.2.501 Yang M, Sun H, Lai H, Hurtado J, Chen Q (2018) Plant-produced Zika virus envelope protein elicits neutralizing immune responses that correlate with protective immunity against Zika virus in mice. Plant Biotechnol J 16(2):572–580. https://doi.org/10.1111/pbi.12796 Yusibov V, Rabindran S (2008) Recent progress in the development of plant derived vaccines. Expert Rev Vaccines 7(8):1173–1183. https://doi.org/10.1586/14760584.7.8.1173 Zakeri B, Fierer JO, Celik E, Chittock EC, Schwarz-Linek U, Moy VT, Howarth M (2012) Peptide tag forming a rapid covalent bond to a protein, through engineering a bacterial adhesin. Proc Natl Acad Sci USA 109(12):E690–E697. https://doi.org/10.1073/pnas.1115485109 Zhao H, Tan Z, Wen X, Wang Y (2017) An improved syringe agroinfiltration protocol to enhance transformation efficiency by combinative use of 5-azacytidine, ascorbate acid and Tween-20. Plants 6(1):9. https://doi.org/10.3390/plants6010009 Zhou J-Y, Cheng L-Q, Zheng X-J, Wu J-X, Shang S-B, Wang J-Y, Chen J-G (2004) Generation of the transgenic potato expressing full-length spike protein of infectious bronchitis virus. J Biotechnol 111(2):121–130. https://doi.org/10.1016/j.jbiotec.2004.03.012