Biopharmaceuticals in Plants: Toward the Next Century of Medicine
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Exclusive web offer for individuals. Toward the Next Century of Medicine. Add to Wish List. Toggle navigation Additional Book Information. Summary Transgenic plants present enormous potential to become one of the most cost-effective and safe systems for large-scale production of proteins for industrial, pharmaceutical, veterinary, and agricultural uses.
Accompanied by an exhaustive list of references to facilitate further study, this critical volume: Describes the theory and practice of modern plant transformation techniques with respect to nuclear and plastic genomes Outlines the steps involved in the generation of transgenic plants Discusses the engineering of plant virus expression vectors for transient expression of vaccine proteins and other therapeutics in plant tissue Addresses the significant role of glycosylation in the production of plant-made mammalian proteins Investigates the basis of mucosal immunity using plant-based oral vaccines Examines the scale-up of plant-derived vaccine and therapeutic proteins in entire crops or in large batch cell suspension cultures Explores the development of clinical trials utilizing plant-derived biopharmaceutical proteins Evaluates risks and biosafety concerns regarding plant-derived pharmaceuticals The book concludes with a discussion of the future of plant-based vaccines and other therapeutic proteins with respect to commercial viability and as a tool to improve global public health.
Reviews "This book serves as an excellent introduction to biopharmaceuticals and as a source of references for those wanting more details. Simmonds, in The Journal of Experimental Agriculture , , volume 47 I "Today, molecular farming represents an extremely heterogeneous field, due to the large variety of different production hosts examined and further complications derived from the different cultivation systems employed.
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Impressum Abraham and to please their download biopharmaceuticals in PET into our individual email and hormone. This rapid increase in the number of new protein and peptide drugs reflects rapid advances in molecular biology, highlighted by the success of the human genome project that, in turn, will help to identify many additional opportunities for therapeutic intervention.
Unfortunately, our capacity to produce these proteins in the quantities needed is expected to fall far short of demand by the end of the current decade. Number of biopharmaceuticals under development, by disease class as of Number of biopharmaceuticals under development, by type of agent.
Advances in plant biotechnology have already resulted in plants that produce monoclonal antibodies or other therapeutic proteins, or that may serve as a source of edible vaccines. Research now underway will almost certainly result in GE plants designed to produce other therapeutic agents including hormones e.
These proteins or peptides possess therapeutic value themselves, have properties that allow them to be used as precursors in the synthesis of medicinal compounds, or may serve as technical enzymes in pharmaceutical production.
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This review will attempt to catalogue the potential therapeutic applications of plant biotechnology and to address concerns related to the safety and efficacy of these agents in relation to human health and to specific disease states. Plant biotechnology can lead to the commercial production of pharmacologically important proteins which are, in many cases, fully functional and nearly identical to their mammalian counterparts. Biopharmaceutical production in plants necessitates a series of careful decisions regarding three critical areas: There are a number of gene expression strategies that can be used to produce specific proteins in plants.
With transient expression TE , a gene sequence is inserted into plant cells using plant viruses, ballistic gene-gun , or other methods, without incorporation of the new genetic material into the plant chromosome. TE systems can be rapidly deployed and can produce large amounts of protein, 2 but because non-chromosomal DNA is not copied with the process of mitosis or meiosis, gene expression is neither permanent nor heritable. While TE systems are very useful for research and development, and may be useful for drug production, they require the fresh production of transformed plants with each planting and may be less attractive for long-term or high-volume protein production.
Alternatively, the primary plant chromosome can be altered to allow for the permanent and heritable expression of a particular protein, i. This can be done using Agrobacterium tumefaciens , a pathogen of plants that, in nature, transfers genetic material to the plant chromosome. By modifying the genetic content of Agrobacterium , desired genes can be readily inserted into many kinds of plants, especially dicots such as soybean.
Biopharmaceuticals in Plants : Toward the Next Century of Medicine.
While permanent modification of the plant genome is more costly and time-consuming, it offers the clear advantage of stable, ongoing protein production with repeated planting alone. Finally, systems exist that modify chloroplast DNA in plants and that can lead to heritable changes in protein expression.
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These tiny energy-producing organelles appear to possess advantages over nuclear transformation, particularly given that each cell may carry hundreds or thousands of such organelles, resulting in the ability to sustain very high numbers of functional gene copies. Consideration must also be given to where within the plant a pharmaceutical protein is to be produced. Current technology allows gene expression and protein production in either the green matter of the plant whole plant expression or selectively in the seed or other tissues through the use of selective promoter systems.
Tuber or root production, while feasible, shares many of the characteristics of green matter production systems. Unlike green matter, seeds generally contain fewer phenolic compounds and a less complex mixture of proteins and have specifically evolved to provide for stable, long-term storage of proteins and other materials in order to assure successful, delayed germination. It is also necessary to decide which plant species to transform for production of a specific pharmaceutical product.
While nearly any plant could theoretically be transformed, practical considerations suggest the use of plants with which we are most familiar, and which already have well-established techniques for genetic transformation, high volume production, harvest, and processing. For green matter production, tobacco has usually been the material of choice, largely because of its highly efficient production of biomass, 2 although other systems such as alfalfa and even duckweed show promise.
Food crop plants have been bred specifically to produce highly productive stands of high-protein seed for which harvesting, processing, and storage technologies are already available. Further, techniques for genetic modification of these plants are well understood, and the extensive history of cultivation and genetic research provides both an understanding of genetic stability and a pool of genetic resources such as the ability to control pollination using the classical C-male-sterile gene in corn , which facilitate production.
This makes food crops highly attractive, with soybean and maize corn being the obvious choices.
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This choice, while highly rational, does lead to the potential for the unintended presence of therapeutic protein in human food, and thus necessitates carefully controlled production to avoid the inadvertent presence of therapeutic material in foods, as discussed below. Drug research is a unique multi-disciplinary process leading to the development of novel therapeutic agents for disease states that have unmet needs.
There are several factors to consider for the safety testing of a new biopharmaceuticals. Nevertheless, both Good Laboratory Practice and Good Manufacturing Practice, as established for other modes of pharmaceutical production, are essential to plant made pharmaceuticals. Before experimental or clinical use is initiated, it is critical to have fully-characterized, contaminant-free materials, as well as appropriate quality assurance so that both the product itself and the therapeutic results will be reproducible.
New pharmaceutical agents derived through plant biotechnology must be subjected to the same purity, quality-control, and safety standards as materials derived from bacterial or mammalian cell systems or from other traditional sources such as vaccine production. Sites used for the cultivation of genetically modified plants have in some cases been disrupted or destroyed by individuals opposed to the use of plant biotechnology, raising additional security concerns. In part, these concerns can be addressed via increased field site monitoring and security, and the use of enclosed environments greenhouses for small scale operations.
The relatively small scale and favourable economics of biopharmaceutical operations allows the placement of field operations in geopolitical locations selected for optimal security, with subsequent shipping of raw or processed materials. Transgenic plants have the added safety feature of freedom from human or animal pathogens. Endotoxins are often difficult to remove and can contaminate a final product. Thus, there is intrinsic safety and value in using plants as a source of recombinant protein. Safety evaluations must consider possible non-target organ responses as well as the entire gamut of anticipated and unanticipated side-effects as with any bio-pharmaceutical product.
Somewhat unique to plant-produced pharmaceuticals are potential effects on non-target species such as butterflies, honeybee, and other wildlife at or near the growing sites. Fortunately, in most instances, the effect on non-target species is limited by the fact that proteins are a normal part of the diet, are readily digested, and are degraded in the environment. Further, many biopharmaceuticals proteins, especially antibodies, are highly species-specific in their effects. Pharmaceutical production in plants may create the potential for the flow of pharmaceutical materials into the human food chain, especially when food crops are used.
This could occur as a result of inadvertent cross-contamination of foodstuffs, through spontaneous growth of genetically engineered plants where they are not desired, or by virtue of pollen flow with some plants e. While some have therefore suggested restricting pharmaceutical production to non-food crops such as tobacco, it is the food crops that present the greatest opportunities for efficient production of biopharmaceuticals and that will be most useful for the production of edible vaccines.
Because of the potential for adventitious presence in food, care must be exercised in the production of biopharmaceuticals in food crops. Unlike commodity crops, plant production of pharmaceuticals should be performed only under tightly controlled conditions similar to those of other pharmaceutical manufacturing; and production standards have been developed jointly by industry, USDA, FDA, and international organizations. FDA required Good Manufacturing Practice necessitates extensive control of field access, harvest, and product disposition. While production controls are necessary and appropriate, it should be kept in mind that the majority of therapeutic proteins are not anticipated to have any pharmacological activity when ingested, and are thus unlikely to present a safety issue in the event of accidental contamination of foodstuffs.
For example, antibodies, insulin, growth hormone, and most other proteins produce few, if any, systemic pharmacological effects by the oral route. This does not preclude the possibility of local effects on the gastro-intestinal tract or the possibility of immunological effects, as seen in the context of oral vaccines, where such an effect is introduced by design. In fact, one plant-derived antibody directed against epithelial cellular adhesion molecules was withdrawn from clinical development as a result of gastro-intestinal side-effects believed to be due to binding to the relevant antigen, which is expressed in the GI tract.
While a case-by-case determination of risk will be necessary when considering proteins for food crop applications, it appears that the majority of proteins would present no great hazard to the public in the event that control technologies should fail to be fully effective. There are a number of recent comprehensive review articles pertaining to production technologies used for molecular farming in plants.
Monoclonal antibodies mAbs have been critical both for the development of biotechnology itself and as products for both therapeutic and diagnostic purposes. Traditional therapeutic monoclonal antibodies have been derived from mice. These proteins were readily identified by the human immune system as foreign, limiting the utility of these antibodies for therapeutic use, especially with repeated dosing.
However, recombinant technologies have allowed murine antibodies to be replaced with partially humanized or chimeric antibodies, and now allow the production of fully human antibodies.