Mapp Bio’s Ebola Drug Shows Promise, But Making More Will Take Time

8/15/14Follow @bvbigelow

The experimental drug therapy given to two Americans and a Spaniard stricken with the lethal Ebola virus was still in research studies when the Ebola outbreak erupted this year in West Africa.

Most of the available material was “laboratory-grade, not human-grade,” said Erica Ollman Saphire, a structural biologist whose lab at The Scripps Research Institute helped San Diego-based Mapp Biopharmaceutical identify antibody targets on the surface of the Ebola virus.

A human trial was scheduled for 2015, and the small amount of human-grade material that was produced has been exhausted, Saphire said. It will take months to make more, because it was derived from genetically engineered tobacco plants that require months to grow.

Structural Biologist Erica Ollman Saphire, TSRI, Ebola

Erica Ollman Saphire

Saphire, an expert in X-ray crystallography, talked with Xconomy by phone yesterday from upstate New York, where she’s on vacation. She is director of a global consortium that includes 25 research institutes in seven countries working to discover new products and techniques for diagnosing and treating Ebola and related viral hemorrhagic fevers. The NIH provided a five-year grant in March for as much as $28 million to identify monoclonal antibodies that can be used to fight Ebola and related viruses.

ZMapp, the drug developed by Mapp Bio that was administered to the three Christian aid workers, is a drug cocktail that combines three “humanized” monoclonal antibodies. Mapp Bio and the U.S. Army Medical Research Institute of Infectious Diseases had developed one of the monoclonal antibodies, Sapphire said. The other two came from the Public Health Agency of Canada.

Mapp Bio provided the doses of ZMapp that were given earlier this month to Dr. Kent Brantly and Nancy Writebol, the volunteer missionaries who were helping to care for Ebola patients in Liberia. Both were airlifted back to the U.S. after they were given ZMapp, and admitted to a special isolation unit at Emory University hospital in Atlanta.

Brantly is expected to be released soon, according to a statement yesterday from the Christian aid group Samaritan’s Purse, and Writebol is reported to be improving.

Word that Brantly and Writebol had received a little-known drug set off a media frenzy, with some news reports referring to ZMapp as a “secret serum.”

Mapp Bio, founded in 2003 by longtime colleagues Kevin Whaley and Larry Zeitlin, has just nine employees and has been funded solely by government grants and contracts. Zeitlin told The New York Times’ Andy Pollock earlier this month the urgency of the global health crisis has been “absolutely overwhelming.” They have been working to make the drug available to people as quickly and safely as possible, and are avoiding the limelight by limiting their public comments to terse, occasional statements posted on Mapp Bio’s website.

The antibody constituents used to make ZMapp have been known for years, Saphire said.

ZMapp combines  monoclonal antibodies (blue, green, yellow) that bind to surface of Ebola virus (courtesy TSRI)

ZMapp combines monoclonal antibodies (blue, green, yellow) that bind to surface of Ebola virus (courtesy TSRI)

Each monoclonal antibody binds to a different site on the surface protein of the thread-like Ebola virus, which replicates by attaching itself to the surface of human cells and seizing control. By combining the three antibodies in an optimized formulation, Saphire says ZMapp both neutralizes the virus and alters the immune system to mount its own defenses.

However, the formulation of constituents that became ZMapp was identified for the first time in January, according Mapp Bio. The work has not even been reported in the scientific literature yet, Saphire said.

While the drug was being advanced for medical use, Saphire said scientists working with Ebola kept tabs on what was out there, should it ever be needed—including “that inevitable moment when someone sticks themselves with a needle” tainted with Ebola. She indicated that at the beginning of the year, the scientists at Mapp Bio and Defyrus, a bio-defense company in Toronto, expected to produce what was needed more or less on their own schedule, as the R&D community needed it.

By the time world health authorities realized they were dealing with an unprecedented outbreak of Ebola in West Africa, ZMapp had only been tested in monkeys that had been deliberately infected with lethal doses of the virus. Mapp Bio, through its collaboration with Defyrus and LeafBio, a San Diego commercialization partner, had a limited batch of the drug—apparently enough to treat only a handful of people, according to The New York Times.

“They’ll have to grow another greenhouse full of tobacco plants to make more ZMapp,” Saphire said. Monoclonal antibodies also can be produced in algae and tissue culture, she said, but that would take time too.

While several experimental drugs are being developed for Ebola, Saphire indicated that health authorities have good reasons to bring Mapp Bio’s drug to the forefront of efforts to get the outbreak in West Africa under control.

Some other treatments have had to be administered within 30 minutes of exposure to the virus to be effective, she said. But in tests with monkeys, she said ZMapp was administered as long as three days after the animals were infected with a very high dose of Ebola virus—and all of the monkeys survived. Saphire said the antibody cocktail even showed some effect on monkeys that were treated several days later, after they had developed Ebola symptoms.

“The antibodies also looked really good from a compassionate use and humanitarian standpoint,” Saphire said. “We know how to make antibodies, we know how they work, and we know there is often less danger of toxicity compared with other types of drugs.”

Liberia said Monday it would get doses of ZMapp to give to two sick doctors, making them the first Africans to receive the scarce treatment as the death toll continues to mount. According to the latest report on the CDC website, health authorities have confirmed at least 1,069 deaths from Ebola in Guinea, Liberia, Nigeria, and Sierra Leone.

The San Diego biotech also provided ZMapp for a Spanish priest, Miguel Pajares, who died in a Madrid hospital five days after he was airlifted from Liberia—where he also was caring for Ebola patients.

In a statement posted on its website earlier this week, Mapp Bio said the available supply of its still-experimental drug therapy has been exhausted. The company has it would take months to produce even modest quantities.

Time is a factor because the Ebola virus causes an extremely virulent disease, which leads to death in 25 to 90 percent of the cases. The virus spreads by direct contact with the blood or other bodily fluids of an infected person.

Meanwhile, a Canadian drug developer, Tekmira Pharmaceuticals, has developed an experimental drug treatment that uses RNA interference to silence genes in the Ebola virus. The Vancouver, BC-based company says it is looking into ways that its experimental Ebola treatment might be used to combat the outbreak in West Africa, even though the drug hasn’t been formally cleared by the various regulatory agencies. Another RNA drug developer, Cambridge, MA-based Sarepta Therapeutics, has said it also has an experimental Ebola drug that could be deployed if regulators would allow it. The company discontinued work on the drug in 2012 amid hangups with defense grants that had been funding the program.

In the most recent statement on its website, Mapp Bio says: “We have complied with every request for ZMapp that had the necessary legal/regulatory authorization. It is the requestors’ decision whether they wish to make public their request, acquisition, or use of the experimental drug. Any decision to use ZMapp must be made by the patients’ medical team. Drug has been provided at no cost in all cases.”

Bruce V. Bigelow is the editor of Xconomy San Diego. You can e-mail him at bbigelow@xconomy.com or call (619) 669-8788 Follow @bvbigelow

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  • http://www.northcoastbio.com Johnny T Stine

    In my little antibody company, with just two 4 liter spinner flasks, I can make 1 gram of each of these antibodies in about 10 days. Making large amounts of these recombinant antibodies cannot possibly be the problem. How many patients could I treat with 1 gram of each of these antibodies using such a minimal effort?