With the seemingly miraculous recovery of two American missionaries infected with the Ebola virus while treating patients in Liberia, ZMapp, the experimental drug that appears to have cured Dr. Kent Brantly and Nancy Writebol of the deadly disease, has rushed to the spotlight.
Aside from the highly unusual fact that it had been tested only on monkeys, ZMapp has another distinction that has drawn attention: It’s engineered in tobacco leaves in a process called biopharming.
Most FDA-approved drugs that involve antibodies, vaccines and other proteins are produced in animal cells farmed in expensive bioreactors. But starting in the 1980s, scientists discovered they could also engineer proteins in plant cells.
As was the case with ZMapp, many companies settled on the tobacco plant as the ideal host for bioengineered proteins because it grows so quickly and produces a high yield.
“It is not the same plant as the tobacco that is smoked,” explained Jean-Luc Martre, a spokesman for Medicago, a Quebec-based company jointly owned by Mitsubishi Tanabe Pharma America and Phillip Morris International.
Rather, it’s a close cousin called Nicotiana benthamiana, a plant native to Australia.
Medicago is using the Nicotiana plant to create vaccines for seasonal and pandemic flu in its 97,000-square-foot facility in North Carolina, both of which are undergoing clinical trials.
“We like to stay with the tobacco plant because it’s not a food crop,” said Chris Hall, chief technology officer of PlantForm, another Canadian company that is also using the tobacco plant to produce a plant-made version of a breast cancer drug that’s similar to Herceptin. “We grow it indoors, in a controlled environment, and we keep any genes from moving out into the environment.”
The technology is still relatively new, but since the late 1980s, a handful of biotech companies around the globe have been experimenting with using everything from tobacco to alfalfa to corn to engineer proteins for pharmaceuticals far faster and cheaper than in animal cells. The U.S. Department of Defense even got involved, with an eye toward quickly and inexpensively ramping up production in the face of pandemic threats.
Tobacco leaves, for example, can produce a large amount of antibodies within six to seven days, according to Hall. “This was an instantaneous thing,” he said.
“Plants happen to address both of those interests, both speed and cost,” said Robert Erwin, president of iBio, a Delaware-based biotechnology company that is using tobacco to develop an H1N1 flu vaccine that’s sponsored by DARPA and is in early-stage human clinical trials. And iBio’s experimental malaria vaccine is being backed by the Gates Foundation.
Erwin said that, compared with scaling up production of antibodies in animal cells, which is slow and difficult, with plants, “you can expand the front end very quickly just by growing more plant capacity.”
Not to mention that building giant bioreactors for engineering animal cells is expensive. According to Hall, the cost of PlantForm’s production system is about one-eighth the cost of building an animal cell production facility with similar capacity. “It’s early days,” he said, but “we feel that this method will reduce costs and will allow us to move into the production phase much quicker.”
While he thinks the animal cell bioreactor way of doing it won’t go away and is “very good,” “as this new technology proves itself and gains strength, it will become another way of doing it.”
But with deep pockets, pharmaceutical companies haven’t had the incentive to develop drugs more cheaply, according to Erwin. Additional production costs can be recouped through pricing.
“Pharmaceutical or biotech companies can literally charge anything they want for their drugs, which up to a certain point is way beyond what anyone would think is reasonable,” he said.
Brazil’s government has partnered with iBio to use its plant technology to produce a yellow fever vaccine, because Brazil hasn’t invested so heavily in animal-made drugs, as some other countries have. Seeking an innovative, lower-cost solution, then, makes sense.
“They don’t have a big infrastructure already built, and they’re very concerned with cost of health care and the cost of biologics,” Erwin said. “It may be that the world is introduced [to plant-made pharmaceuticals] through the commitments of countries like Brazil.”
The urgency of a rare disease has certainly sped up the process. In 2012, Elelyso became the first plant-made drug to be approved by the FDA for the treatment of Gaucher disease, a rare genetic enzyme deficiency that can cause anemia and bone deterioration. An Israeli biotech company, Protalix Biotherapeutics, uses modified carrot cells to produce the drug.
The FDA fast-tracked Elelyso’s approval because of a shortage of Cerezyme, another drug approved to treat Gaucher, due to production problems in 2009 and 2010 with drug maker Genzyme. And with a year’s supply of Cerezyme reportedly costing an eye-popping $200,000, Elelyso’s price tag is 25 percent less because of cheaper production costs, according to Protalix.
But plant-made pharmaceuticals, like genetically modified foods, haven’t been without controversy.
In the early 2000s, a Texas-based biotech company, ProdiGene, was hailed for the innovative edible vaccines, made in modified corn kernels, that it was developing for hepatitis B and E. coli.
But in 2002, ProdiGene faced an unanticipated disaster: Its modified corn was believed to have bred with the corn in a nearby field in Iowa and narrowly missed entering the food supply. It also contaminated soybean crops in Nebraska. ProdiGene had to destroy the crops and ended up paying an estimated $3 million in cleanup costs and fines to the U.S. Department of Agriculture, according to The Wall Street Journal.
And in 2006, a federal court in Hawaii ruled that the USDA’s Animal and Plant Health Inspection Service should have done more due diligence before giving companies such as Monsanto and ProdiGene permits to plant their modified corn and sugar cane in Hawaii. The crops were to be used to make experimental drugs and vaccines, but advocacy groups Earthjustice and the Center for Food Safety sued the USDA, saying the agency’s oversight had been lax in taking into account their effects on Hawaii’s endangered species.
Still, with the Ebola epidemic shedding light on the benefits of plant-made pharmaceuticals, the companies that are making them hope the interest in ZMapp will push the industry forward. “This is probably the way of the future for vaccine production, as far as we’re concerned,” said Medicago's Martre. While he added that it’s too early to promise huge cost savings, the speed at which the vaccines can be produced is a major advantage, and “certainly our technology will be on the economical side.”
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