New Investments Revive Hopes for Plant-Made Pharmaceuticals

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New investments by two different pharmaceutical companies in programs to manufacture biologics in tobacco plants are reviving hope in the promise of plant-made pharmaceuticals.

New investments by two different pharmaceutical companies in programs to manufacture biologics in tobacco plants are reviving hope in the promise of plant-made pharmaceuticals. Both companies use transient expression, making these systems much faster than production methods that require growing transgenic plants.

The Canadian biotechnology firm Medicago (Quebec City) announced on September 23 that the tobacco company Philip Morris International (PMI) invested $16 million in Medicago to fund the development of Medicago’s pandemic and seasonal influenza vaccines, which are produced in tobacco plants. Less than a week later, on September 29, Bayer Innovation GmbH (Leverkusen, Germany), a subsidiary of Bayer AG, announced a partnership with Kentucky Bioprocessing (KBP, Owensboro, KY) to develop a facility at KBP’s Owensboro site to process proteins from tobacco plants.

Under the agreement with Bayer, KBP will install Bayer’s proprietary system for high throughput transfection of tobacco host plants. This transient expression system, called “Magnicon,” uses the tobacco mosaic virus as a vector to transfect the gene of interest into a soil bacterium, Agrobacterium tumfaciens. The agrobacterium enters the tobacco plants through an infusion process. First, the plants are placed upside down in a bath containing the bacterium. A vacuum is applied, which draws out the air from the spaces between the plant’s cells, and then draws the solution into the plant through its pores. The plants are then returned to the greenhouse to grow for a specified amount of time before harvesting and purifying the protein from the leaves.

KBP’s main role will be automating the infusion process. “Right now the infusion is done manually,” said Hugh Haydon, chairman of the board of KBP. “We are automating and increasing the scale of the process to produce the proteins in commercial volumes."

The first product Bayer is seeking to produce in tobacco plants is a patient-specific antibody vaccine for non-Hodgkin’s lymphoma. To create the vaccine, a section of the patient’s tumor would be removed, then the antigens on the tumor surface would be amplified through the plant-based production process. The tumor antigens would then be put back into the patient along with a foreign protein, keyhole limpet hemocyanin.

Katharina Jansen, PhD, a Bayer spokesperson, says the time between diagnosis of the tumor and treatment is expected to be less than three months. “The plants don’t become specialized until we transfect them,” she says. “So we can have a lot of tobacco plants growing and ready ahead of time.”

Bayer also opened a pilot plant in June, in Halle, Germany, for this product, and hopes to begin Phase 1 trials for the cancer vaccine next year. The company is also working on a project to produce flu vaccines in tobacco, in partnership with the Swiss company AmVac.

Medicago: Pandemic Influenza Vaccine in 30 Days
Medicago’s production system is very similar to the one used by Bayer, involving inserting the gene of interest into A. tumfaciens, then infusing the plants in a vacuum process. The company is using the method to produce a virus-like particle vaccine for pandemic influenza.

The system’s speed is one of its key advantages, according to Frederic Ors, vice president of business development for Medicago. “We can go from identification of the antigen to having a vaccine in just a month,” he said, compared to about six months for egg-based systems, and three months for traditional cell-based manufacturing methods.

It takes one week to synthesize the antigen sequence, another week to create the master cell bank, then two weeks for the remaining steps, including inoculating the plants, allowing the plants to grow for about five days, harvesting the leaves, and purifying the protein.


The other advantage is cost. The company’s small-scale facility in Quebec City was built for about $4 million, and Ors estimates that it will cost about $15 to $20 million to construct a commercial-scale site-about a tenth of the cost of a traditional biomanufacturing facility. Operating costs are also about 10 times lower than traditional set ups, he says.

These lower costs, he believes, will elicit interest not only from emerging countries, but also from developed countries who want to build surge capacity to prepare for a potential pandemic outbreak. “There is a significant unmet need for systems to produce vaccines for pandemic influenza,” he said. Medicago is currently in “advanced discussions” to build facilities in three countries, including France, and unnamed countries in Asia and North Africa.

Medicago expects to begin toxicology studies early next year, and file for an IND in June.

Promise of Plant-Made Pharmaceuticals?
Although plant-made pharmaceuticals were once hailed as the solution to the high-cost of traditional biomanufacturing, no plant-made drugs have been commercialized yet.

Ajaz Hussain, PhD, vice president of biological systems for PMI R&D, says the lack of success is due to a complex set of factors.

First, he says, some of the early efforts came out of agricultural operations, and the
people involved did not fully recognize the challenges posed by developing pharmaceutical products, in terms of the extensive product characterization and analytics needed. Second, much of the initial focus was on oral vaccines, which present many challenges such as standardizing the dose. That may be possible in the future, he said, but it was too difficult a problem to tackle at the beginning.

Third, because plant-based systems are very different from traditional biologics manufacturing operations, it was difficult for larger companies to see how they could integrate the two. In addition, most large pharmaceutical companies already had a lot of investment in traditional systems, so they did not have a strong incentive to invest in alternatives.

Another concern sometimes raised about plant-based systems is the differences in glycosylation patterns in plants and humans.

Hussain sees two ways of looking at that question. The first is to find technology solutions to modify plant glycosylation patterns to make them more human-like, which some companies like Biolex are already doing. The other is to leverage the differences by understanding how these differences impact the safety and efficacy of vaccines.