Tobacco-derived ‘plantibodies’ enter the fight against Ebola

NEW YORK — Drugmakers’ use of the tobacco plant as a fast and cheap way to produce novel biotechnology treatments is gaining global attention because of its role in an experimental Ebola therapy.

The treatment, which had been tested only in lab animals before being given to two American medical workers in Liberia, consists of proteins called monoclonal antibodies that bind to and inactivate the Ebola virus.

For decades biotech companies have produced such antibodies by growing genetically engineered mouse cells in enormous metal bioreactors. But in the case of the new Ebola treatment ZMapp, developed by Mapp Pharmaceuticals, the antibodies were produced in tobacco plants at Kentucky Bioprocessing, a unit of tobacco giant Reynolds American.

The tobacco-plant-produced monoclonals have been dubbed “plantibodies”.

“Tobacco makes for a good vehicle to express the antibodies because it is inexpensive and it can produce a lot,” said Erica Ollmann Saphire, a professor at The Scripps Research Institute and a prominent researcher in viral haemorrhagic fever diseases like Ebola. “It is grown in a greenhouse and you can manufacture kilogrammes of the materials. It is much less expensive than cell culture.”

In the standard method of genetic engineering, DNA is slipped into bacteria, and the microbes produce a protein that can be used to combat a disease.

A competing approach called molecular “pharming” uses a plant instead of bacteria. In the case of the Ebola treatment, Mapp uses the common tobacco plant, Nicotiana benthanmianas.

The process is very similar. A gene is inserted into a virus that is then used to infect the tobacco plant. The virus acts like a micro-Trojan Horse, ferrying the engineered DNA into the plant.

Cells infected with the virus and the gene it is carrying produce the target protein. The tobacco leaves are then harvested and processed to extract the protein, which is purified.

ZMapp’s protein is a monoclonal antibody, which resembles ordinary disease-fighting antibodies but has a highly specific affinity for particular cells, including viruses such as Ebola. It attaches itself to the virus cells and inactivates them.

Approval process

The drug so far has only been produced in very small quantities, but interest in it is stoking debate over whether it should be made more widely available to the hundreds of people stricken with Ebola in Africa while it remains untested.

“We want to have a huge impact on the Ebola outbreak,” Mapp CEO Kevin Whaley said in an interview at company headquarters in San Diego. “We would love to play a bigger role.”

Whaley said he was not aware of any significant safety issues with the serum. He would not discuss whether the company has been contacted about providing the drug overseas.

But he did note the novel manufacturing process carries its own risk, and would have to be cleared by the US Food and Drug Administration as part of the approval process.

The FDA would, for example, have to be satisfied that the plant extraction process had not led to contamination of the resulting drug.

The tobacco plant grows quickly, said Reynolds spokesman David Howard, and “it takes only about a week (after the genes are introduced) before you can begin extracting the protein.”

He declined to say how much medication each plant can yield or whether Kentucky Bioprocessing is in a position to produce ZMapp in significant quantities.

Scripps’ Saphire said it can still take anywhere from one to three months to produce the ZMapp serum for wider use given the complexities of the process.

Pentagon funding

In 2007, Kentucky Bioprocessing entered into an agreement with Mapp Biopharmaceutical and the Biodesign Institute of Arizona State University to refine the tobacco-plant approach. The approach attracted funding support from the Pentagon’s Defence Advanced Research Projects Agency (DARPA).

For all the hope, however, the plant technique has delivered few commercial products. In 2012 the FDA okayed a drug for the rare genetic disorder Gaucher disease from Israel’s Protalix BioTherapeutics and Pfizer. Called Elelyso, it is made in carrot cells, and is the only such drug to reach the market.

Other companies have fallen far short, though it is not clear if the technique was to blame. Calgary-based SemBioSys Genetics Inc., which used safflowers to produce an experimental diabetes drug, folded in 2012 before it finished clinical trials.

Even Kentucky Bioprocessing, which at one point was developing monoclonal antibodies against HIV (the virus that causes AIDS), C. difficile bacterial infection, and the human papillomavirus, has dropped the last two projects, Howard said.

Last year Mitsubishi Tanabe Pharma Corp. acquired a majority share of Quebec City-based Medicago, which is developing influenza and other vaccines using the tobacco-plant technology. The other 40 per cent is owned by tobacco giant Philip Morris International.