Human monoclonal therapeutic antibodies based on plant systems for human use.

MAbs may be produced in cultured mammalian cells, such as CHO, SP2/0 or NSO cells, human cell lines such as PER-C6 or HEK, as well as in bacterial cells, yeast, fungi, plants or cultured plant cells. The preparation may be generated from cells or plants producing only mAb fragments or genetically altered mAbs. Following purification, the mAbs or mAb fragments can be further modified to alter their pharmacokinetic and/or pharmacodynamic profiles. The microbiological risks of plant-derived substrates may be substantially different from those involved in animal-derived reagents and other hazards may arise – such as immunogenic, mitogenic and allergenic properties of the reagent and its components. Plant-derived material may, for instance, carry an increased risk of mycoplasma and mycobacteria contamination ²⁴.

In recent years, progress has been made in using plants as an expression system to produce biologics and vaccines, including recombinant therapeutic proteins, which is referred to as Plant Molecular Farming (PMF). The recombinant proteins, including mAbs, can be produced in plants by stable expression, transient expression and transgenic plant cell expression in plant cells. Plants can make post-translational modifications similar to those of human and mammalian cells, but this results in a different glycosylation pattern than substrates from animal or human cells. However, the difference in glycosylation patterns of plant-derived proteins can be overcome by glycoengineering in plants to obtain humanised proteins²⁵.

Development of plant cell substrate-based biologics hold promising potential.

In light of the current Coronavirus pandemic, developing plant-derived candidate vaccines and biologics against emerging coronavirus infections may provide a platform with a huge potential, which has been reviewed by Shanmugaraj et al., 2021²⁶ Though none of the SARS-CoV-2-related products/vaccines as reported have been authorized for market yet, and are currently either under research or in preclinical phases and/or phase I/II clinical trials. Meher Un Nessa et al., 2020²⁷ present a total of 53 research articles reporting the action of plant-produced monoclonal antibodies as immunotherapy for cancer, illustrating 200 phase 1, 110 phase 2 and 33 late stage clinical phase for antibody development. Numerous plant species which can proficiently engineered for mAb production include Nicotiana benthamiana, Nicotiana tabacum, Arabidopsis thaliana and others, while the highest biomass yield was found in tobacco species. Tobacco is a non-food, non-feed, and well-specified expression system, excluding human pathogen contamination, which can decrease biosafety concerns²⁸.

The Coronavirus pandemic as well as increasing global vaccine demand are requiring high vaccine manufacturing capabilities. Better utilization of currently used cell substrates, but also the introduction of novel cell substrates may provide higher vaccine yields and thus may contribute to meeting production targets satisfying worldwide supply. Different vaccine types, most importantly live attenuated virus vaccines manufactured in cell substrates require highest cell substrate characterization with regards to identity, stability, purity, adventitious agents/viruses, tumorigenicity and oncogenicity.

There is still a lack of standardisation and harmonisation of the various guidance documents around the world, although the relevant guidance documents are constantly being revised to represent the latest and most modern technologies, which also reflect knowledge based on historical data. The lack of harmonisation is a challenge for biologics and mAbs, but also for vaccine manufacturers who want to deliver globally in order to obtain regulatory approval for these cell-based vaccines.

The question is: Would plant-derived biologics/vaccines and/or monoclonal antibody production facilitate or reduce the effort of thorough characterisation of cell substrates and accelerate the knowledge base, leading to faster regulatory acceptance of these plant-derived biologics - OR - are we "opening a can of worms" (microbiological, random pathogens, immunogenic, tumorigenic, oncogenic, mitogenic, allergenic properties)? We will see!

At any rate, the WHO, the Expert Committee on Biological Standardization (ECBS) has started to provide guidance on mAbs manufactured from genetically engineered transgenic plant-based systems and is seeking public consultation and input for their guidance.

I think, this is a good first step into the right direction.