Research into producing inexpensive, plant-based therapeutic proteins, antibodies, and vaccines is making quiet progress, yet commercialization remains to be seen due to environmental opposition, high R&D costs, and regulatory and industry uncertainty.
But the promise is enticing: Common crops such as corn, tobacco, lettuce, and soybeans can be genetically modified to produce antibodies, antigens, growth factors, hormones, enzymes, blood proteins, collagen, and other therapeutic proteins, demand for which is estimated to reach $18 billion over the next 20 years. By some estimates, 200 acres of genetically modified (GM) corn could produce the same quantity of drugs as a $400 million factory using standard cell fermentation systems. Other studies suggest pharmed proteins could be produced at 10% of the cost of microbial systems and 0.1% of mammalian cell cultures.
But the hurdles and uncertainties involved in bringing plant-produced therapies to market have led most of the major pharmaceutical companies and agricultural giants to abandon pharming, while many smaller biotech companies have either shut down or been acquired by competitors. As a result, only a handful of small companies and universities worldwide continue to plow this field of research.
But persistence might pay off. Two recent studies reported this summer point to where pharming is headed, if the barriers can be overcome.
A team of researchers successfully completed a Phase 1 human trial of the first plant-produced vaccine for non-Hodgkin’s lymphoma. Using a tobacco mosaic virus expression vector supplied by the now-defunct Large Scale Biology Corp., Vacaville, Calif., researchers from Stanford University, Palo Alto, Calif., Bayer HealthCare, Berkeley, Calif., and several consultancies produced patient-specific recombinant idiotype vaccines against follicular B-cell lymphoma.
The researchers took biopsies from each lymphoma patient, isolated and patched the gene for the B-cell surface immunoglobulin into the virus expression vector, and scratched the virus onto the leaves of a tobacco plant, where it began to express. After a week, the plant was harvested and the protein was purified and injected into the patient. More than 70% of the patients developed cellular or humoral immune responses and 47% of the patients developed antigen-specific responses, according to the study published in the July 22 Proceedings of the National Academy of Sciences (PNAS).
“These findings support the conclusion that plant-produced idiotype vaccines are feasible to produce, safe to administer and a viable option for idiotype-specific immune therapy in follicular lymphoma patients,” said Charles J. Arntzen, PhD, founding director of the Center for Infectious Diseases and Vaccinology at Arizona State University’s Biodesign Institute in Tempe, who edited the PNAS paper.
A group of researchers at the University of Central Florida’s (UCF) College of Medicine in Orlando, Fla., successfully completed the first animal test of a plant-derived oral vaccine against plague (Yersinia pestis). Henry Daniell, PhD, and his team developed the vaccine using tobacco chloroplasts to overexpress recombinant proteins during leaf development.
The vaccine was administered to mice both orally and by injection. All unvaccinated mice died within three days of being exposed to high doses of aerosolized plague, while 88% of those given the oral vaccine and 33% of the injected mice survived. “We are very excited because it appears the oral vaccine is even more effective than traditional injectable vaccine,” Daniell said. “This could really make a difference.”
Human trials are still needed, but Daniell is confident the chloroplast technology can also produce vaccines for the bubonic and pneumonic plagues. Results of his NIH- and USDA-funded research were published in the August 2008 issue of Infection and Immunity. UCF has spun off a for-profit company, Chlorogen Inc. (St. Louis, Mo.) to commercialize Daniell’s patented chloroplast-based technology. Chlorogen is collaborating with Kentucky BioProcessing LLC (Owensboro), a contract research and manufacturing company, to scale up development of a potential ovarian cancer drug also produced in tobacco.
In the 1990s, the concept of pharming held great appeal to drug and biotech companies, scientists and investors, anticipating that plant-produced proteins would be less expensive and potentially safer than those produced by traditional mammalian and microbial cell culture methods. At the time, more than 180 companies and organizations were involved in pharming research. But environmental opposition, regulatory uncertainties, and improvements in fermentation techniques have since dampened enthusiasm. Pfizer, Eli Lilly, Novartis, and others have spun off or disposed of their agriculture-biotech drug divisions.
Further complicating matters, in 2003 US Department of Agriculture (USDA) tightened environmental restrictions on outdoor pharmed crops after a small quantity of GM corn grown for ProdiGene Inc. (College Station, Texas) in Nebraska the year before was detected in a soybean crop from the same field the following season. USDA now requires outdoor pharmed crops to be kept at least one mile from other food crops and be inspected at least seven times before being harvested with dedicated equipment.
Today, most pharming research in the US has gone indoors to environmentally- secure greenhouses or even underground to prevent accidental pollination. Ventria Bioscience (Ft. Collins, Colo.), is an exception, growing genetically modified rice in Kansas farmland to produce bacteria-fighting enzymes lactoferrin and lysozyme found in breast milk and saliva. Potential uses are for pediatric diarrhea and topical infections, especially in developing nations.
Closer to market is SemBioSys Genetics Inc. of Calgary, Alberta, Canada. The company has produced commercial levels of human insulin from GM protein-coated lipospheres or oilbodies of safflower seeds grown in Chile. According to the company, the FDA has said it would allow an abbreviated 505b2 drug approval process and doesn’t anticipate “unexpected issues” from using GM safflower as a production system. The company hopes to begin clinical trials this year.
Closer still may be Biolex Therapeutics Inc., Pittsboro, N.C., which recently completed a Phase 2 clinical trial of controlled-release interferon alpha in Hepatitis C patients. The drug is produced by genetically modified Lemna, an aquatic plant also known as duckweed.
About the Author
Contributing editor Ted Agres, MBA, is a veteran science writer in Washington, DC. He writes frequently about the policy, politics, and business aspects of life sciences.
This article was published in Drug Discovery & Development magazine: Vol. 11, No. 10, October, 2008, pp. 10-12.
Filed Under: Drug Discovery