Ebola Drug’s Success Bolsters Approach for Other DiseasesJohn Lauerman and Caroline Chen
An experimental drug given to two U.S. health workers infected with Ebola may help raise the profile of an immune strategy that’s already shown promise against other diseases, including HIV.
The Mapp Biopharmaceutical Inc. drug, called ZMapp, is an antibody cocktail designed to block the virus from entering cells. The strategy was thought to be best at preventing infections, but ZMapp’s outcomes in animals, and now possibly humans, suggests the antibodies may treat the sick as well.
While it’s too early to say the Mapp drug works, the attention may help speed development of antibody-based treatments against other diseases, including HIV-AIDS, responsible for an estimated 1.6 million deaths globally in 2012, and drug-resistant bacterial infections, the killer of about 23,000 people in the U.S. each year.
“There may be a bit of a revolution going on,” said Dennis Burton, an immunology professor at the Scripps Research Institute in La Jolla, California. “Maybe antibodies can do more than we thought they could.”
Antibody-based treatments such as Roche Holding AG’s Herceptin have been well established in cancer therapy. Now drugmakers led by Gilead Sciences Inc. and Pfizer Inc. are looking at expanding the treatment’s influence in other ways.
Neutralizing antibodies work by latching onto viruses, interfering with their ability to invade host cells. Vaccines against diseases such as smallpox, measles and whooping cough trigger the body to make its own antibodies well in advance of infection.
In the case of ZMapp, the antibodies were given directly to the patients already made. Kent Brantly, a doctor, and Nancy Writebol, an aid worker, received the drug after they were infected while working at an Ebola center in Liberia. Families and supporters have said both are improving.
“The preliminary information coming out suggests that the antibodies had value in a full-blown Ebola virus infection,” said Scripps’s Burton. “That challenges the dogma that antibodies are not so great once the infection is roaring.”
There is no cure for Ebola. The disease is normally treated by keeping patients hydrated, replacing lost blood and using antibiotics to fight off opportunistic infections. The hope is that a patient’s immune system will eventually fight off the virus’s aggressive attack. About 60 percent of patients have died in the current outbreak.
Ebola is like “a burglar trying to break into a luxury mansion,” said Kartik Chandran, associate professor at the Albert Einstein College of Medicine at Yeshiva University in New York. “It’s figured out how to pick the locks and how to cut all the wires to the cameras.”
Chandran’s research focuses on finding antibodies that can block the virus’s access. A decade ago, there were few studies that suggested the antibodies were very effective, so follow-up efforts were rare, he said in a telephone interview.
If media reports suggesting that the drug was given more than a week after the patients’ infections occurred are true, that would have given the virus a fairly long time to replicate in the body, he said.
“Assuming it did work, I’m a little surprised that it would be so effective so late,” he said.
Much more experience with patients is needed to show that the drug is useful, said Michael Diamond, an infectious disease researcher at Washington University School of Medicine in St. Louis. Almost half of the people who get Ebola virus recover on their own, and the two Americans who got the drug may fall into that category, Diamond said.
Mapp’s approach was already raising eyebrows before its use in the Ebola outbreak in Africa that, according to the World Health Organization, has infected 1,848 and killed 1,013, as of Aug. 9. In a 2012 study, the cocktail of three neutralizing antibodies protected monkeys as long as two days after they were infected with Ebola or Marburg virus, a related disease.
Such results from antibody treatment were “once thought impossible,” said Darryl Falzarano and Heinz Feldmann of the U.S. National Institute of Allergy and Infectious Diseases’ Laboratory of Virology in Hamilton, Montana.
Antibody treatments “have taken the lead in terms of survival and delayed treatment,” for Ebola and Marburg, they said in a commentary published in April in the journal Cell Research.
Scientific tools to identify, isolate, modify and produce powerful antibodies have revealed new drug potential for the proteins, said Gary Nabel, chief scientific officer of Paris-based Sanofi and a former director of the U.S. Vaccine Research Center in Bethesda, Maryland.
For example, Seattle-based Theraclone Sciences has excellent technology for isolating highly unusual antibodies with useful disease-fighting properties, Nabel said.
Theraclone has developed techniques for analyzing the immune cells of patients with “interesting” responses to infections, and identifying antibodies that can clear the body of invasive agents, said Chief Executive Officer Clifford Stocks.
“We can pinpoint exactly the one or few antibodies that are responsible for neutralizing the pathogen,” Stocks said in a telephone interview.
The company is developing an antibody-based treatment for severe flu cases that is in the second of three stages of human testing needed for U.S. market clearance. Closely-held Theraclone is also joining with New York-based Pfizer to develop neutralizing antibodies-based treatments for drug-resistant bacterial infections, Stocks said.
Pfizer remains focused on prevention, spokesman Dean Mastrojohn said in an e-mail: “Our R&D focus in infectious diseases has shifted from treatment to prevention, and on applying our leading expertise in vaccine technology to this important area which we believe will enable us to have the most profound impact on patients’ lives.”
Theraclone announced July 30 that Gilead, the biggest maker of HIV drugs, had bought exclusive rights to develop products based on Theraclone’s neutralizing antibodies.
It is a new type of therapy for Gilead, which is based in Foster City, California, Cara Miller, a spokeswoman, said in an e-mail. She declined to give more details about the program.
Burton and colleagues at Harvard University and Beth Israel Deaconess Medical Center in Boston published studies of animals last year showing that treatment with neutralizing antibodies lowered viral measurements of a monkey version of HIV to levels where they were no longer detectable. While that doesn’t mean the virus is no longer in the body, its similar to the levels achieved by standard anti-HIV drug treatments.
“The concept of antibody therapy for HIV infections is a very fast-moving field,” said Dan Barouch, a professor of medicine at Harvard and Beth Israel who led the 2013 study. “It’s now being considered very seriously in a number of different settings.”
One of the advantages of neutralizing antibodies is that they attack viruses in the bloodstream and on the surface of cells. Most HIV drugs, while highly effective in most patients, only confront viruses once they’ve entered cells and begun replication. A combination of the two types of treatment might be particularly effective, Barouch said.
“We don’t know if these antibodies will be able to be part of an HIV eradication or cure regimen,” he said.
The work being done with Ebola may help speed up development of treatments that will help quell future outbreaks, Chandran said.
“This outbreak is incredible and horrible, but I’m optimistic that things will accelerate now, and we can get treatments and a vaccine to market in the next few years,” Chandran said.