Therapeutic recombinant protein production in plants: Challenges and opportunities

Abstract

Societal Impact Statement Therapeutic protein production in plants is an area of great potential for increasing and improving the production of proteins for the treatment or prevention of disease in humans and other animals. There are a number of key benefits of this technique for scientists and society, as well as regulatory challenges that need to be overcome by policymakers. Increased public understanding of the costs and benefits of therapeutic protein production in plants will be instrumental in increasing the acceptance, and thus the medical and veterinary impact, of this approach. Summary Therapeutic recombinant proteins are a powerful tool for combating many diseases which have previously been hard to treat. The most utilized expression systems are Chinese Hamster Ovary cells and Escherichia coli, but all available expression systems have strengths and weaknesses regarding development time, cost, protein size, yield, growth conditions, posttranslational modifications and regulatory approval. The plant industry is well established and growing and harvesting crops is easy and affordable using current infrastructure. Growth conditions are generally simple: sunlight, water, and the addition of cheap, available fertilizers. There are multiple options for plant expression systems, including species, genetic constructs and protein targeting, each best suited to a particular type of therapeutic protein production. Transient expression systems provide a mechanism to rapidly transfect plants and produce therapeutic protein in a matter of weeks, rather than the months it can take for many competing expression systems, while proteins targeted to cereal seeds can be harvested, stored and potentially purified much more easily than in competing systems. Current challenges for plant expression systems include a lack of regulatory approval, environmental containment concerns and nonhuman glycosylation, which may limit the scope of the type of therapeutic proteins that can be manufactured in plants. The specific strengths of plant expression systems could facilitate the production of certain therapeutic proteins quickly and cheaply in the near future.

Plant Molecular Farming: A Viable Platform for Recombinant Biopharmaceutical Production

“…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 [1]. Many plant-produced therapeutic proteins are in pre-clinical and clinical trials and are close to commercialization [23,24].…”

“…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 [1]. 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.…”

“…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 [1,5,6]. 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.…”

Genetic and process engineering strategies for enhanced recombinant N-glycoprotein production in bacteria

“…Production in mammalian cells, predominantly in the Chinese Hamster Ovary (CHO) cell, enables coupling of complex mammalian glycans to glycoproteins at an industrial-scale [28,29]. However, costly manufacturing processes, heterogeneous products, and risk of viral contamination remain a significant challenge for production in mammalian cell lines [30][31][32]. Functional transfer of the pgl locus from C. jejuni into E. coli opened up a new area of bacterial glycoengineering [15].…”

Enabling Transgenic Plant Cell–Derived Biomedicines with Nanotechnology

“…[ 54 ] Due to the absence of glycosylation pathways, chloroplasts are only amenable to producing proteins that do not require glycosylation to function, although such chloroplast‐derived proteins are less immunogenic. [ 55 ] While gene delivery to chloroplasts traditionally entails the use of a gene gun because of the double‐membraned barrier of chloroplasts, NPs provide new opportunities for bypassing the delivery hurdle. Wong et al postulated a mathematical model called lipid exchange envelope penetration (LEEP) to predict the trafficking of NPs to chloroplasts, based on the assumption that the electrostatic interactions between the NP and chloroplast membrane contribute to softening of the membrane and delivery of NPs to the chloroplast.…”