Noah Machakos
Table of Contents
Why Plants Are the Future of Biologics: The Science Behind Recombinant Protein Drugs
Introduction
Biologics—the creation of recombinant protein drugs—have been revolutionary in treating complex diseases. They provide targeted therapies for conditions including cancer and autoimmune disorders. Over the past 50 years, scientists have produced these complex proteins in mammalian cells, bacterial cultures, yeast, and plants.
Throughout the 2010s and into the 2020s, plant-based biologics emerged as a promising alternative to traditional mammalian platforms, offering advantages such as cost-effectiveness, scalability, and reduced risk of contamination by human pathogens. This article explores the benefits and challenges of transient expression in plants—particularly in Nicotiana benthamiana, the protein foundry used by us at Molecular Pharming Solution.
The Rise of Biologics and Recombinant Proteins
Advanced therapeutic protein designs mimic proteins produced by our immune systems—such as antibodies and cytokines—and are engineered to treat disease by targeting cellular receptor mechanisms. These therapeutic proteins are long chains of 20 naturally occurring amino acids whose chemical properties enable folding and receptor binding (Lagattuta et al., 2025)
Biologics manufacturing is fundamentally about DNA: triplets of nucleotides (codons) map to amino acids, enabling near-limitless protein designs. Modify the DNA, and you can modify the amino acid sequence to create proteins with specialized functions. The development of recombinant DNA technology enabled large-scale production of recombinant protein drugs and transformed therapy (Walsh, 2018). Recombinant human insulin is one example; pembrolizumab (an anti–PD-1 immunotherapy) is another.
Traditional platforms include Chinese hamster ovary (CHO) cells, Escherichia coli, and Saccharomyces cerevisiae (yeast). CHO remains the dominant system and has proven effective but costly—and those costs reach patients. For example, the list price for some leading checkpoint inhibitors given every 6 weeks is in the tens of thousands of dollars per dose.
Why Use Plants for Biopharmaceuticals?
1) Cost-Effectiveness and Scalability
Mammalian cell culture demands costly bioreactors, nutrient media, and highly sterile operations. Plants, by contrast, can be grown at scale in controlled greenhouses and vertical farms while maintaining excellent quality (Rybicki, 2017). Classic comparisons of CHO vs. N. benthamiana have long highlighted the potential for lower cost of goods (Ma et al., 2005).
2) Lower Risk of Contamination
Animal-derived cell cultures carry a non-zero risk of adventitious human pathogen contamination (e.g., viruses). While all systems require rigorous controls, plants are naturally less permissive to many human pathogens, which can reduce certain contamination risks common to mammalian cell culture (Barone et al., 2020).
Why Molecular Pharming Solution: Our CDMO services will take care of you throughout the entire value chain. Molecular Pharming Solution can work with you to provide initial construct design as well as GMP protein production. Our tested platform ensures seamless integration throughout all stages of biopharmaceutical development. Our fully-fledged cGMP facility in Bangkok also enables clinical and commercial production which meets strict international standards.
3) Rapid Production and Agile Scale-Up
Agrobacterium-mediated transient expression can deliver recombinant protein yields within weeks—much faster than typical CHO scale-up (Gleba et al., 2005). This speed contributed to the rapid development of ZMapp, a plant-made antibody cocktail for Ebola (Qiu et al., 2014). During COVID-19, N. benthamiana was used to rapidly produce vaccine candidates, such as Medicago’s plant-derived VLP program and other plant-based SARS-CoV-2 antigens (Ruocco & Strasser, 2022). Baiya Phytopharm, the parent company of Molecular Pharming Solution, also reported positive preclinical data for an N. benthamiana–produced vaccine candidate (Phoolcharoen et al., 2023).
4) Glycosylation Advantages (and Engineering Control)
Post-translational modifications (PTMs) like glycosylation and disulfide bond formation can differ in plants versus mammalian cells, and those differences affect function and PK/PD (Friso & van Wijk, 2015). Modern glycoengineering in N. benthamiana enables mammalian-like glycan profiles—and even tailored glycoforms for improved properties (Chen, 2016).
Methods of Producing Recombinant Proteins in Plants
Stable Transformation
Stable transformation integrates recombinant DNA into the plant genome for expression across generations. It can be suitable for long-term production but often faces complex regulatory pathways for genetically modified crops that vary by country and use case.
Transient Expression Systems
Transient expression offers rapid, high-yield production without genome integration. The most common method is Agrobacterium-mediated transient expression: Agrobacterium tumefaciens delivers DNA coding for the protein of interest (e.g., pembrolizumab) into plant cells, where it is expressed episomally (Phakham et al., 2021). Deconstructed viral vectors and optimized expression cassettes further boost yield and speed (Peyret & Lomonossoff, 2015).
Challenges and Future Directions
Regulatory approval. Pathways for plant-made pharmaceuticals (PMPs) continue to mature. A landmark study demonstrated regulatory approval and a first-in-human trial of a plant-derived monoclonal antibody, building confidence in PMPs (Ma et al., 2015).
Glycosylation differences. Continued comparability data are needed for specific products and indications. Advances in glycoengineering are enabling human-like glycans and bespoke glycoforms for function and PK optimization (Friso & van Wijk, 2015); (Chen, 2016).
Immunogenic glycan motifs. Removing plant-specific β(1,2)-xylose and α(1,3)-fucose has been demonstrated in N. benthamiana to mitigate immunogenicity risks and improve similarity to human glycosylation, with additional engineering enabling specialized O-glycan patterns (Daskalova et al., 2010).
Conclusion
Plant-based expression systems offer a powerful route to produce recombinant protein drugs. With rapid transient expression, deepening glycoengineering toolkits, and maturing regulatory precedent, global adoption of plant-made biologics can expand access, reduce costs, and accelerate innovation. At Molecular Pharming Solution, we are eager to be a part of driving this transformation forward throughout the decades to come.
References
Barone, P. W., Wiebe, M. E., Leung, J. C., Hussein, I. T. M., Keumurian, F. J., Bouressa, J., … Plavsic, M. (2020). Viral contamination in biologic manufacture and implications for emerging therapies. Nature Biotechnology, 38(5), 563–572. https://doi.org/10.1038/s41587-020-0507-2
Chen, Q. (2016). Glycoengineering of plants yields glycoproteins with polysialylation and other defined N-glycoforms. Proceedings of the National Academy of Sciences, 113(34), 9404–9406. https://doi.org/10.1073/pnas.1610803113
Daskalova, S. M., Radder, J. E., Cichacz, Z. A., Olsen, S. H., Tsaprailis, G., Mason, H., & Lopez, L. C. (2010). Engineering of Nicotiana benthamiana L. plants for production of N-acetylgalactosamine-glycosylated proteins—Towards development of a plant-based platform for protein therapeutics with mucin-type O-glycosylation. BMC Biotechnology, 10, 62. https://doi.org/10.1186/1472-6750-10-62
Friso, G., & van Wijk, K. J. (2015). Posttranslational protein modifications in plant metabolism. Plant Physiology, 169(3), 1469–1487. https://doi.org/10.1104/pp.15.01378
Gleba, Y., Klimyuk, V., & Marillonnet, S. (2005). Magnifection—A new platform for expressing recombinant vaccines in plants. Vaccine, 23(17–18), 2042–2048. https://doi.org/10.1016/j.vaccine.2005.01.006
Lagattuta, K. A., Nathan, A., Rumker, L., Birnbaum, M. E., & Raychaudhuri, S. (2025). The T cell receptor sequence influences the likelihood of T cell memory formation. Cell Reports, 44(1), 115098. https://doi.org/10.1016/j.celrep.2024.115098
Ma, J. K.-C., Barros, E., Bock, R., Christou, P., Dale, P. J., Dix, P. J., … Twyman, R. M. (2005). Molecular farming for new drugs and vaccines: Current perspectives on the production of pharmaceuticals in transgenic plants. EMBO Reports, 6(7), 593–599. https://doi.org/10.1038/sj.embor.7400470
Ma, J. K.-C., Drossard, J., Lewis, D., Altmann, F., Boyle, J., Christou, P., … Stöger, E. (2015). Regulatory approval and a first-in-human phase I clinical trial of a monoclonal antibody produced in transgenic tobacco plants. Plant Biotechnology Journal, 13(8), 1106–1120. https://doi.org/10.1111/pbi.12416
Peyret, H., & Lomonossoff, G. P. (2015). When plant virology met Agrobacterium: The rise of the deconstructed clones. Plant Biotechnology Journal, 13(8), 1121–1135. https://doi.org/10.1111/pbi.12412
Phakham, T., Bulaon, C. J. I., Khorattanakulchai, N., Shanmugaraj, B., Phoolcharoen, W., & Boonkrai, C. (2021). Functional characterization of pembrolizumab produced in Nicotiana benthamiana using a rapid transient expression system. Frontiers in Plant Science, 12, 736299. https://doi.org/10.3389/fpls.2021.736299
Phoolcharoen, W., Shanmugaraj, B., Malaivijitnond, S., Srisutthisamphan, K., Khorattanakulchai, N., Rattanapisit, K., … Chaotheing, S. (2023). Preclinical evaluation of immunogenicity, efficacy and safety of a recombinant plant-based SARS-CoV-2 RBD vaccine formulated with 3M-052-Alum adjuvant. Vaccine, 41(17), 2781–2792. https://doi.org/10.1016/j.vaccine.2023.03.027
Qiu, X., Wong, G., Audet, J., Bello, A., Fernando, L., Alimonti, J. B., … Kobinger, G. P. (2014). Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature, 514(7520), 47–53. https://doi.org/10.1038/nature13777
Ruocco, V., & Strasser, R. (2022). Transient expression of glycosylated SARS-CoV-2 antigens in Nicotiana benthamiana. Plants, 11(8), 1093. https://doi.org/10.3390/plants11081093
Rybicki, E. P. (2017). Plant-made vaccines and reagents for the One Health initiative. Human Vaccines & Immunotherapeutics, 13(12), 2912–2917. https://doi.org/10.1080/21645515.2017.1356497
Walsh, G. (2018). Biopharmaceutical benchmarks 2018. Nature Biotechnology, 36(12), 1136–1145. https://doi.org/10.1038/nbt.4305