How plantibodies are revolutionising the world of biopharmaceuticals.

By Easha Vigneswaran

The use of plants in medical technology has been exploited by scientists for many years. In the nineties, the discovery plant use to manufacture antibodies provided a new insight into how we can use plants to benefit the pharmaceutical world.

Antibodies are complex molecules called immunoglobulins, responsible for the attenuation of pathogenic molecules to neutralise toxins. They are antigen specific and recognise receptors on the pathogen to then allow the immune system to respond accordingly. Antibodies have been isolated and used to treat a variety of illnesses including inflammation, autoimmune diseases, and other infectious diseases (Dwek, 2009). During the nineties, the idea of using plants as a host to produce antibodies was conceived, and later got the term ‘plantibodies’ (Oluwayelu & Adebiyi, 2016). These are genetically modified plants that have been engineered to produce antibodies, much like those produced by humans in an immune response. 

To produce the transgenic plants, the bacterium Agrobacterium tumefaciens was used. The ability of the Agrobacterium to undergo horizontal gene transfer was harnessed as a means of introducing its genes into plant cells. The bacterium is known to cause the plant disease ‘crown gall’ which is cancerous in plants and produces tumour like growths on the plant body. To cause the tumour, the bacterium transfers its DNA (T-DNA) through a tumour inducing plasmid (Ti plasmid) into the plant cell which is then incorporated into the plant cell’s nucleus. Once T-DNA is expressed in the plant, it results in the loss of cell control and, therefore, in the formation of tumours (Gelvin, 2005). By manipulating the bacterium and plants’ ability to undergo horizontal gene transfer, scientists were able to genetically engineer the Ti-plasmid containing T-DNA for an alternative target gene. Transfer of the different gene products allows scientists to manipulate the plants’ abilities to have pathogen resistance or, in this case, induce drug production for human use (Gelvin, 2005). 

Another method that was used to produce plantibodies was based on the use of two viral vectors from two different types, the tobacco mosaic virus and potato Virus X (Chen, 2021). Two viral vectors are necessary, where one viral vector would produce the heavy chain of the antibody and the other vector produces the lighter chain resulting in the full-size functional antibody. The benefit of this method was that the recombination of antibody expression was much faster, and the yield proved much greater than using a bacterium  (Fischer, Twyman & Schillberg, 2003). 

As for the plant host, there are ideal criteria the plant should meet: it must be possible to genetically engineer it; be able to produce a high yield of the desired proteins; the technology to undergo gene transfer and the knowledge of its agriculture should exist; it has no toxic side effects on the human body. Therefore, a popular plant host is the tobacco plant (Nicotiana benthamiana or Nicotiana tabacum) due to their high yield and large biomass. The plant also has many growing seasons and can therefore be produced throughout the year. The main downside of this species is the presence of toxins (Shakya et al., 2018). Other species that have been used include cereals, tubers, and tomatoes although these often prove less economically advantageous for mass production comparatively to the tobacco plant.

The discovery of using transgenic plants as a way of producing antibodies proved very advantageous. One of the most obvious advantages is the fact that using plants is much more cost effective. The production of transgenic plants is easier than the far more highly regulated production in animals (Oluwayelu & Adebiyi, 2016). Another key advantage is that, in general, plant pathogens are not dangerous to humans so there is no risk of human infection from the genetically modified plant. The ease of mass production of plants makes it far more attractive as a means of producing antibodies due to the higher yields and the fact that plants mature faster than animal hosts will. Harnessing seeds is also easier with plants meaning the production of mutant plant strains with the ability to produce these antibodies is more reproducible (Sharma et al., 2004).

However, with all the benefits, it would be naïve to ignore there are also obvious disadvantages with plants. The primary downfall with using plants is the evident genomic differences between the pathogenic prokaryotes and plants. This may result in the inexpression of certain proteins or the production of different polysaccharides due to the differences in the genetic codes. Plants also produce allergenic compounds that may induce negative immune results when trying to use certain antibodies with humans (Sharma et al., 2004).

The manipulation of this technology has been applied in a variety of medical therapeutics. The first time a major clinical trial went underway using plantibody technology was with the secretory immunoglobulin A (sIgA) antibody which coined the name ‘CaroRx’ produced from the transgenic tobacco plants (Schillberg, Emans & Fischer, 2002). The genetic engineering required four plant strains and was engineered for the targeting of the Streptococcus mutans antigens. S. mutans is responsible for tooth decay and so the plantibody treatment was designed to treat this oral infection to reduce tooth decay by elimination of the bacteria (Fischer, Twyman & Schillberg, 2003).

A more contemporary use of this technology in tobacco plants was also developed as a means of combating the Ebola virus. A viral strain from the geminivirus family commonly found to cause disease in plants was used with the plantibody technology in Nicotiana benthamiana to produce the antibody ‘mAb’ that protected animal species from contracting the infection from the Ebola virus. An Ebola immune complex was formed from the fusion of an Ebola glycoprotein and the ‘mAb’. These modified immunoglobulins were purified from the Nicotiana plant and later injected into mice to observe its effectiveness. It was found to work as an anti-Ebola treatment and so it was developed as drug called ‘ZMapp’ by Mapp biopharmaceuticals, used to treat infected people globally (Prasad et al., 2017).

The genetic modification of plants to produce transgenic species and using them as a source of antibodies is proving to be very popular amongst researchers as a new form of mass-producing drugs. The economical and practical benefits of using plants are undeniable. Low costs and high yields make them an attractive tool for pharmaceuticals and the reproducibility of this technology in numerous crop species make it possible to manufacture drugs in developing countries with significantly less medical technology access. The prospects of plantibody technology show great potential for the biopharmaceutical industry.  

References:

Dwek, R. (2009) Antibodies and antigens: It’s all about the numbers game. Proceedings of the National Academy of Sciences. 106 (7), 2087-2088. Available from: https://www.pnas.org/content/106/7/2087 .[Accessed Jan 25th, 2021].

Oluwayelu, D. O. & Adebiyi, A. I. (2016) Plantibodies in human and animal health: a review. African Health Sciences. 16 (2), 640-645. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27605982. Available from: doi: 10.4314/ahs.v16i2.35. [Accessed Jan 25th, 2021].

Gelvin, S. B. (2005) Gene exchange by design. Nature (London). 433 (7026), 583-584. Available from: https://search.proquest.com/docview/204605270. Available from: doi: 10.1038/433583a. [Accessed Jan 26th, 2021]

Chen, Ed. (2021) Plantibodies. Available from: https://www.biolegend.com/en-us/blog/plantibodies . [Accessed 25th January 2021].

Fischer, R., Twyman, R. M. & Schillberg, S. (2003) Production of antibodies in plants and their use for global health. Vaccine. 21 (7), 820-825. Available from: http://www.sciencedirect.com/science/article/pii/S0264410X02006072. Available from: doi: 10.1016/S0264-410X(02)00607-2. [Accessed Jan 26th, 2021]. 

Shakya, P., Sharma, V., Nayak, A., Jogi, J., Gupta, V., Rai, A., Bordoloi, S., (2018) Plantibodies as biopharmaceuticals: A review. Journal of Pharmacognosy and Phytochemistry. 2072-2074. Available from: https://www.phytojournal.com/archives/2018/vol7issue5/PartAJ/7-5-151-698.pdf . [Accessed Jan 26th, 2021].

Sharma, A.K., Jani, D., Raghunath, C., Tyagi, A.K., (2004) Transgenic plants as bioreactors. Indian Journal Biotechnology. Vol 3. 274-290. Available from: http://nopr.niscair.res.in/handle/123456789/5856 . [Accessed Jan 26th, 2021].

Schillberg, S., Emans, N. & Fischer, R. (2002) Antibody molecular farming in plants and plant cells. Phytochemistry Reviews 1, 45–54. Available from: https://doi.org/10.1023/A:10158802186 . [Accessed Jan 25th, 2021].

Prasad, M., Brar, B., Jyothi, M., Shah, I., Ranjan, K., Lambe, U., Prasad, G., (2017) Plantibodies for Global Health: Challenges and Perspectives. Biotechnology for Sustainability Achievements. 305-321. Available from: https://www.researchgate.net/publication/318636597_Plantibodies_for_Global_Health_Challenges_and_Perspectives [Accessed Jan 26, 2021].

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