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Sep 25, 2014
 |  BC Innovations  |  Cover Story

Interrupting Ebola

The 2014 Ebola outbreak is the largest in the disease's history and the first in West Africa, where it has reached multiple countries. Although an approved therapy looks far away, five of seven patients given an experimental combination of mAbs are still alive. But that therapy is only one of several in development, and it is all hands on deck now to push the programs into the clinic.

The ZMapp antibody cocktail from Mapp Biopharmaceutical Inc. is a composite of different mAbs that Mapp, Defyrus Inc., the Public Health Agency of Canada and the University of Manitoba have been working on for at least two years.

The pipeline also contains vaccines and oligonucleotides against Ebola and its close relative, Marburg virus (see "Filovirus pipeline"). Researchers polled by SciBX said that the different approaches should be pursued in parallel given the severity and urgency of the outbreak.

"There is a place for all of these different strategies, such as siRNAs, mAb cocktails and vaccines," said Erica Ollmann Saphire. "Different options might be used at different times."

Ollmann Saphire is a professor of immunology and microbial science at The Scripps Research Institute and director of the Viral Hemorrhagic Fever Immunotherapeutic Consortium.

She said that a vaccine, which would generally be used before exposure to the virus, could be given to aid workers, scientists and people living in or near an outbreak. Antibody and siRNA-based therapies would generally be used post-exposure, although pre-exposure antibodies or post-exposure high-dose vaccines might also work.

Now, each of the modalities has received support from three independent studies that showed specific antibodies, vaccines or siRNAs can prevent or treat disease in nonhuman primates.1-3

ZMapp cocktail

ZMapp is being developed as a therapeutic for infected individuals, and although it has been used in a small number of patients on a compassionate use basis, it still has safety hurdles to satisfy in controlled clinical trials.

The cocktail contains two components from the ZMAb antibody mix provided by a team from the Public Health Agency of Canada and University of Manitoba, and one MB-003 component provided by Mapp. The MB-003 mix contained three human or human-mouse chimeric mAbs, whereas ZMAb was a combination of three mouse mAbs targeting Ebola glycoproteins.

In previous work, the Canadian team showed that ZMAb was partially protective in nonhuman primates when given after fever and virus in the blood were detected. Likewise, earlier work by Mapp showed that MB-003-combined with an interferon-α (IFNA; IFN-a)-expressing adenovirus adjuvant-protected 7 out of 8 nonhuman primates when given up to 72 hours after infection.

Now, the Canadian and Mapp researchers have combined components of the two mixes to find a cocktail that has greater efficacy and can extend the treatment window compared with either MB-003 or ZMAb.

The group used a series of Ebola challenge experiments in guinea pigs and nonhuman primates and screened different mAb combinations to find which provides the best antiviral response. The screen yielded two triple-antibody cocktails, ZMapp1 and ZMapp2, that each contained one MB-003-derived and two ZMAb-derived mAbs.

Next, the researchers compared ZMapp1 and ZMapp2 in nonhuman primates in a study of the Ebola Kikwit variant in which the cocktail was given via i.v. administration three times at three-day intervals, three days after infection.

ZMapp1 produced a better outcome than ZMapp2, as it controlled viremia better, and led to survival of six of six rhesus macaques compared with five of six for ZMapp2 and zero of two for mock treatment.

Each of the three ZMapp1 antibodies target different epitopes on the Ebola glycoprotein, which suggested there is a low chance that escape mutants would be a significant problem. Escape mutants occur when replicating viruses accumulate mutations in antibody recognition sites, which reduces the antibodies' ability to neutralize the virus.

In a second Ebola challenge study, ZMapp1 protected 18 of 18 rhesus macaques when given via i.v. administration 3 times at 3-day intervals, even when the cocktail was started 5 days after infection. In addition, the cocktail reversed disease symptoms such as elevated liver enzymes, mucosal hemorrhages and rash.

Although ZMapp1 was not directly tested against the Ebola Guinean strain responsible for the West African outbreak, sequence homology studies and in vitro binding assays suggested the mAbs would have comparable neutralizing activities to those shown against the Kikwit strain.

ZMapp1 is now called ZMapp.

"What we observed in the nonhuman primate studies was beyond all of our expectations," said Gary Kobinger. "The ZMapp-treated rhesus macaques all recovered and show no adverse effects at this time." Kobinger is chief of special pathogens for the Public Health Agency of Canada...

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