Abstract
Plants offer several unique advantages in the production of recombinant pharmaceuticals for humans and animals. Although numerous recombinant proteins have been expressed in plants, only a small fraction have been successfully put into use. The hugely distinct expression systems between plant and animal cells frequently cause insufficient yield of the recombinant proteins with poor or undesired activity. To overcome the issues that greatly constrain the development of plant-produced pharmaceuticals, great efforts have been made to improve expression systems and develop alternative strategies to increase both the quantity and quality of the recombinant proteins. Recent technological revolutions, such as targeted genome editing, deconstructed vectors, virus-like particles, and humanized glycosylation, have led to great advances in plant molecular farming to meet the industrial manufacturing and clinical application standards. In this review, we discuss the technological advances made in various plant expression platforms, with special focus on the upstream designs and milestone achievements in improving the yield and glycosylation of the plant-produced pharmaceutical proteins.
Highlights
Introduction of Humanized NGlycosylation Pathway in PlantsThe lack of human-type N-glycan structures in plants is due to the absence of a collection of enzymes that are responsible for several processes: (1) the addition of core α1,6-fucose residue; (2) the formation of multi-antennary structures; (3) β1,4-galactosylation on the GlcNAc residues; and (4) the subsequent α2,3- or α2,6-sialylation on the galactose residues
Despite the similarities shared between plants and mammals in their protein secretory pathways, low yields and/or diminished biological activity of many recombinant proteins produced in plant cells are still the biggest challenges faced in cross-kingdom expression due to incompatibilities arising from factors such as codon bias [31,32], incorrect or insufficient folding [33,34], non-humanized
By the N-terminal fusion of a chloroplast transit peptide (CTP), such as that found on the RuBisCO small subunit (RbcS) precursor, recombinant proteins are typically targeted to the chloroplast for accumulation
Summary
Using plant-based platforms for the production of high-value recombinant proteins, referred to as plant molecular farming, has been a promising concept since the 1980s, with the goal of making plant-produced pharmaceuticals an alternative for industrial and clinical applications [1,2]. Nicotiana benthamiana is one of the most widely used plant materials for the transient expression of recombinant proteins due to its many favorable attributes, such as fast growth, large biomass, robust reproduction, and easy scalability It is a versatile platform for either quick assays on proof-of-concept designs, or variable scales of fast production of final products, especially in response to epidemic and pandemic threats. It provides a more sustainable and scalable solution for the mass production of recombinant pharmaceuticals [1,27,28] Therapeutic proteins, such as antigens and antibodies, can be expressed and accumulated in the edible parts of the plant, such as the seeds or grains of cereals and legumes, tap roots and tubers, fruits, and leaves of fresh produce, for easy oral delivery, which provides the benefits of easy administration to both human and veterinary pharmaceuticals, and greatly reduces the production cost by minimizing downstream purification and modification [19,28,29]. We highlight the technological advances made in the improved yield and increased quality of plant-made pharmaceutical proteins and discuss how these breakthroughs led to greater industrial and clinical applications from plant molecular farming
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