Plants have been part of medicine for thousands of years, but bioengineering plants to produce therapeutic proteins is changing
the shape of biotech. Plant-made biopharmaceuticals are cheaper to develop and cheaper to produce. Will they take over the
field?
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After many starts and stops, hype and disappointment, foreign protein expression in plants is now routine and biopharmaceuticals
produced in green plants will soon be with us. Plants have been part of medicine for thousands of years and pharmaceuticals
still rely heavily on plant-based materials: more than half of our pharmacopoeia is extracted from plants or related to plant
compounds.
Plant-made biopharmaceuticals (PMBs), however, break the traditional mold of plants and medicines in two ways: plants are
bioengineered, and the resulting protein drugs are foreign to it - just as they are to recombinant yeast or bacteria or to
transfected mammalian cells.
PMBs are preparing the way for the "next wave" in biotech which will parallel the evolution of biotechnology itself. According
to a University of Florida study, more than 300 PMBs are under investigation worldwide.1 Most of this work goes on at academic or government institutions. Eventually, this undercurrent of technology will provide
the foundation for PMB companies, just as it did for biotech 20 years ago.
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PMBs could have a big impact on markets for therapeutic recombinant proteins. The argument for PMBs is compelling. Datamonitor,
a business information company, estimates the world market for therapeutic proteins at about $30 billion, and predicts demand
will rise to $59 billion by 2010.2 Leading the way are monoclonal antibodies, with 2003 sales exceeding $3 billion and growth approaching 60% yearly. The market
for therapeutic vaccines, although of much smaller volume, is also growing quickly, with 61% growth on 2002 sales of $31 million.
Table 1, from Datamonitor's report, lists leading marketed therapeutic proteins.
Moreover, what PMB companies lack in capital funding they more than make up for with innovation and vision. Larry Grill, Ph.D.,
chief scientific officer at Vacaville, CA-based Large Scale Biology Corp. (LSBC), predicts "at least a couple of dozen" approved
plant-based biotech products by 2010. Most managers at PMB firms share his optimism.
Figure 1. These rice plants, developed by Ventria Bioscience, will grow into mature plants and express therapeutic proteins.
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Optimistically, PMBs' lower capital costs and greater production flexibility could simply steal the show. Realistically, PMBs
eventually may dominate specific therapeutic protein markets or monopolize biogenerics. Or they could fail.
Are PMBs Better? On paper at least, PMBs offer numerous advantages over traditional fermentation and cell culture. Among these are
- low capital costs
- lower production costs
- easy scale-up
- simplified downstream processing
- wide applicability to protein types
- potential for small-molecule manufacture
- ability to express several genes simultaneously
- inherent safety, especially of food crops
- easy long-term storage of raw product
- low proteolytic activity in crude product
- environmentally benign
- applicable to all dosage forms
- opportunities for personalized medicine.
Figure 2. Ventria's rice-based PMBs illustrate the basic method of protein expression in plants.
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Compared to traditional biomanufacturing, PMBs offer lower capital investment and lower ongoing manufacturing costs. Brick-and-mortar
plants take from two to seven years to build and cost anywhere from $100 million to $500 million, and this only includes the
cost of the plant, not ongoing manufacturing and other functions. The Dow Chemical Co. and Sigma Aldrich estimate capital
reduction at 75% to 80%, with manufacturing costs slashed 50% to 60%. Neil Cowen, Ph.D., vice president for product development
at Epicyte Pharmaceutical in San Diego believes ongoing cost savings for manufacturing might even reach 75%.
Cost advantages for downstream PMB operations depend on the final dosage form. As with all therapies, injectibles tend to
be high-cost products, while edible or topical PMBs will be cheaper to develop.
Still, potentially significant cost savings are possible downstream. Because of the large biomass expected from PMB processes,
batches will be large enough for developers to consider continuous or semi-continuous processing, which biotech companies
traditionally avoid. A side benefit of large batches is lower quality assurance and quality control requirements since these
activities are performed per batch, not per volume or weight of product.
