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PostPosted: Mon Aug 04, 2014 10:42 am 
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CNN reporting that Americans in Liberia treated with a cocktail of three mouse monoclonal antibodies generated against Ebola (designated as ZMapp).

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PostPosted: Mon Aug 04, 2014 10:45 am 
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VIDEO
(CNN) -- Three top secret, experimental vials stored at subzero temperatures were flown into Liberia last week in a last-ditch effort to save two American missionary workers who had contracted Ebola, according to a source familiar with details of the treatment.
On July 22, Dr. Kent Brantly woke up feeling feverish. Fearing the worst, Brantly immediately isolated himself. Nancy Writebol's symptoms started three days later. A rapid field blood test confirmed the infection in both of them after they had become ill with fever, vomiting and diarrhea.
It's believed both Brantly and Writebol, who worked with the aid organization Samaritan's Purse, contracted Ebola from another health care worker at their hospital in Liberia, although the official Centers for Disease Control and Prevention case investigation has yet to be released.
A representative from the National Institutes of Health contacted Samaritan's Purse in Liberia and offered the experimental treatment, known as ZMapp, for the two patients, according to the source.
The drug was developed by the biotech firm Mapp Biopharmaceutical Inc. The patients were told that this treatment had never been tried before in a human being but had shown promise in small experiments with monkeys.
Second Ebola patient heading to U.S. Doctors struggle to treat Ebola patients Ebola transport team speaks to CNN First American Ebola patient comes home
According to company documents, four monkeys infected with Ebola survived after being given the therapy within 24 hours after infection. Two of four additional monkeys that started therapy within 48 hours after infection also survived. One monkey that was not treated died within five days of exposure to the virus.
Brantly and Writebol were aware of the risk of taking a new, little understood treatment; informed consent was obtained from both Americans, according to two sources familiar with the care of the missionary workers. In the monkeys, the experimental serum had been given within 48 hours of infection. Brantly didn't receive it until he'd been sick for nine days.
The medicine is a three-mouse monoclonal antibody, meaning that mice were exposed to fragments of the Ebola virus and then the antibodies generated within the mice's blood were harvested to create the medicine. It works by preventing the virus from entering and infecting new cells.
The Ebola virus causes viral hemorrhagic fever, which refers to a group of viruses that affect multiple organ systems in the body and are often accompanied by bleeding.
Early symptoms include sudden onset of fever, weakness, muscle pain, headaches and a sore throat. They later progress to vomiting, diarrhea, impaired kidney and liver function -- and sometimes internal and external bleeding.
Vials reach hospital in Liberia
The ZMapp vials reached the hospital in Liberia where Brantly and Writebol were being treated Thursday morning. Doctors were instructed to allow the vials to thaw naturally without any additional heat. It was expected that it would be eight to 10 hours before the medicine could be given, according to a source familiar with the process.
Brantly asked that Writebol be given the first dose because he was younger and he thought he had a better chance of fighting it, and she agreed. However, as the first vial was still thawing, Brantly's condition took a sudden turn for the worse.
Brantly began to deteriorate and developed labored breathing. He told his doctors, "I am going to die," according to a source with firsthand knowledge of the situation.
Knowing his dose was still frozen, Brantly asked if he could have Writebol's now-thawed medication. It was brought to his room and administered through an IV. Within an hour of receiving the medication, Brantly's condition was nearly reversed. His breathing improved; the rash over his trunk faded away. One of his doctors described the events as "miraculous."
By the next morning, Brantly was able to take a shower on his own before getting on a specially designed Gulfstream air ambulance jet to be evacuated to the United States.
Writebol also received a vial of the medication. Her response was not as remarkable, according to sources familiar with the treatment. However, doctors on Sunday administered Writebol a second dose of the medication, which resulted in significant improvement.
She was stable enough to be evacuated back to the United States and is expected to arrive before noon Tuesday.
ZMapp has not been approved for human use, and has not even gone through the clinical trial process, which is standard to prove the safety and efficacy of a medication. The process by which the medication was made available to Brantly and Writebol is highly unusual. It may have fallen under the U.S. Food and Drug Administration's "compassionate use" regulation, which allows access to investigational drugs outside clinical trials.
Getting approval for compassionate use is often long and laborious, but in the case of Brantly and Writebol, they received the medication within seven to 10 days of their exposure to the Ebola virus.
On July 30, the Defense Threat Reduction Agency, an arm of the military responsible for any chemical, biological, radiological, nuclear and high-yield explosive threats, allotted additional funding to MAPP Biopharmaceutical due to "promising results."

http://www.cnn.com/2014/08/04/health/ex ... ?hpt=hp_t2

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PostPosted: Mon Aug 04, 2014 10:51 am 
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Monoclonal Antibody-based Filovirus Therapeutic Licensed to Leaf Biopharmaceutical
Web Site Release July 15, 2014
Toronto, ON - today Defyrus announced an exclusive, worldwide license to their Ebola
therapeutic monoclonal antibody (mAb) patent portfolio to Leaf Biopharmaceutical Inc. of San
Diego, CA. This license expands the commercial relationship between LeafBio and Defyrus who
have been actively collaborating to drive the commercialization of mAb-based Ebola therapies.
LeafBio, the commercialization partner of Mapp Biopharmaceutical, had been developing
proprietary Ebola-specific antibody drug MB-003 in collaboration with the National Institutes of
Health and the Defense Threat Reduction Agency (DTRA). The licensing of Defyrus’ ZMAb
antibody portfolio, pioneered at the Public Health Agency of Canada (PHAC) and licensed earlier
to Defyrus, consolidates the intellectual property of a superior combination mAb drug – termed
ZMapp™ - which is composed of the best mAbs of MB-003 and ZMAb.
Under the terms of the exclusive, worldwide license, LeafBio assumes the commercial
responsibility for the ongoing development of ZMapp™. The two companies have agreed to an
equitable revenue sharing model based on ZMapp™ product sales.
“Integrating key ZMAb antibody technology into our ongoing Ebola virus preclinical and planned
clincial development program has been welcomed by our US government partners” stated Larry
Zeitlin, President of LeafBio. “ZMapp™ has enhanced efficacy as a treatment in our non-human
primate challenge models.”
ZMapp™ antibodies are being produced under an existing manufacturing collaboration with
Kentucky Bioprocessing (KBP, Owensboro KY). Using a fully automated production system that
operates in accordance with good manufacturing practices (GMP), the antibodies are produced in
Nicotiana. This high performance manufacturing process decreases production time, increases
the quantity of antibody produced, and lowers the cost of manufacturing.
“This license to LeafBio places our ZMAb technology in the hands of experienced antibody
manufacturers with specific regulatory expertise and funding. We share a joint vision with
LeafBio to deliver an effective treatment for Ebola virus infection on a cost effective basis
globally.” said Jeffrey Turner, President & CEO Defyrus.
About Defyrus
Defyrus is a Canadian private, life sciences biodefence company that collaborates with military
and public health R&D partners in the United States, Asia and Canada to develop broad
spectrum anti-viral drugs, MAbs and vaccines as medical countermeasures to viral and bacterial
infectious diseases. www.defyrus.com
About Mapp and Leaf Biopharmaceutical
Mapp Biopharmaceutical develops novel biopharmaceuticals for the prevention and treatment of
infectious diseases, focusing on unmet needs in global health and biodefense. As these products
transition to clinical evaluation, Leaf Biopharmaceutical assumes ownership and
commercialization responsibilities.
www.mappbio.com, www.leafbio.com

For further information:
Dr. Jeffrey D. Turner Dr. Larry Zeitlin
President & CEO President
Tel: (613) 674-1138 Tel: (800) 372-2176
info@defyrus.com larry.zeitlin@leafbio.com

http://www.mappbio.com/ZMAb.pdf

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PostPosted: Mon Aug 04, 2014 11:13 am 
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EMBARGOED FOR RELEASE: CONTACT: Caree Vander Linden
August 21, 2013 – 2:00 PM Eastern Time (301) 619-2285
Fort Detrick, Maryland Caree.VanderLinden@us.army.mil
Experimental Ebola Treatment Protects Some Primates Even After Disease Symptoms Appear
Scientists have successfully treated the deadly Ebola virus in infected animals following
onset of disease symptoms, according to a report published online today in Science Translational
Medicine. The results show promise for developing therapies against the virus, which causes
hemorrhagic fever with human case fatality rates as high as 90 percent.
According to first author James Pettitt of the U.S. Army Medical Research Institute of
Infectious Diseases (USAMRIID), the research team previously demonstrated that the
treatment—known as MB-003—protected 100 percent of non-human primates when given one
hour after Ebola exposure. Two-thirds of the animals were protected when treated 48 hours after
exposure.
In the current study, 43 percent of infected non-human primates recovered after receiving
the treatment intravenously 104 to 120 hours after infection. The experimental design differed
significantly from the team’s earlier work—this time, infected animals were not treated until they
developed measurable symptoms of disease.
Ebola virus has been responsible for numerous deaths in Africa over the past several
years. In addition to being a global health concern, the virus also is considered a potential
biological threat agent.
“By requiring both a documentable fever and a positive diagnostic assay result for Ebola
infection before initiating treatment in these animals, we were able to use MB-003 as a true
therapeutic countermeasure,” said senior author Gene Olinger, Ph.D., of USAMRIID. “These
initial results push the threshold of MB-003 from post-exposure prophylaxis to treating verified
illness.”
According to the scientists, Ebola virus replicates quickly to very high levels, thus
overwhelming the host’s ability to fight off the infection. MB-003 is a “cocktail” of monoclonal
antibodies that help bind to and inactivate the virus. In addition, said Pettitt, the antibodies
recognize infected cells and trigger the immune system to kill them off. No side effects of the
antibodies were observed in the surviving animals.

MB-003 was developed through a decade-long collaborative effort between private
industry and the U.S. government, with funding from the Defense Advanced Research Projects
Agency (DARPA), the National Institutes of Health (NIH), and the Defense Threat Reduction
Agency (DTRA).
“With no vaccines or therapeutics currently licensed to treat or prevent Ebola virus, MB-
003 is a promising candidate for continued development,” said collaborator Larry Zeitlin, Ph.D.,
president of Mapp Biopharmaceutical in San Diego, California.
MB-003 is manufactured in a plant-based system by Kentucky BioProcessing in
Owensboro, Kentucky. According to Barry Bratcher, the company’s chief operating officer, the
plant-based system allows for considerable efficacy while KBP’s automated facility keeps MB-
003 cost-effective and cuts down on the production time required.
“Our facility can produce these proteins in two weeks at a substantial reduction in cost to
other production methods,” said Bratcher. “This advanced method of manufacturing allows us to
address needs quickly and inexpensively.”
Zeitlin said Mapp recently announced formation of a joint venture between LeafBio
(Mapp’s commercialization arm) and Defyrus of Toronto, Canada, to consolidate their antibody
programs. He said the relationship will streamline development of the most potent anti-filovirus
products.
According to Zeitlin, the next step in the drug development process would be to more
extensively test the safety of the antibodies in animals. Once that is established, the safety of the
antibodies would need to be assessed in human volunteers. Ultimately, a large efficacy study in
non-human primates and a larger safety study in humans would be required for Food and Drug
Administration (FDA) licensure of the product.
USAMRIID’s mission is to protect the warfighter from biological threats and to be
prepared to investigate disease outbreaks or threats to public health. Research conducted at
USAMRIID leads to medical solutions—vaccines, drugs, diagnostics, and information—that
benefit both military personnel and civilians. The Institute plays a key role as the lead military
medical research laboratory for the Defense Threat Reduction Agency’s Joint Science and
Technology Office for Chemical and Biological Defense. USAMRIID is a subordinate
laboratory of the U.S. Army Medical Research and Materiel Command.
###
Reference: J. Pettitt, L. Zeitlin, D. H. Kim, C. Working, J. C. Johnson, O. Bohorov, B. Bratcher,
E. Hiatt, S. D. Hume, A. K. Johnson, J. Morton, M. H. Pauly, K. J. Whaley, M. F. Ingram,
A. Zovanyi, M. Heinrich, A. Piper, J. Zelko, G. G. Olinger. Therapeutic intervention of Ebola virus
infection in rhesus macaques with the MB-003 monoclonal antibody cocktail.
Sci. Transl. Med. 5, 199ra113 (2013)
For more information about USAMRIID: www.usamriid.army.mil
No commercial endorsement is implied.

http://www.leafbio.com/PettittAug2013.pdf

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PostPosted: Mon Aug 04, 2014 11:18 am 
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Sci Transl Med. 2013 Aug 21;5(199):199ra113. doi: 10.1126/scitranslmed.3006608.
Therapeutic intervention of Ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail.
Pettitt J1, Zeitlin L, Kim do H, Working C, Johnson JC, Bohorov O, Bratcher B, Hiatt E, Hume SD, Johnson AK, Morton J, Pauly MH, Whaley KJ, Ingram MF, Zovanyi A, Heinrich M, Piper A, Zelko J, Olinger GG.
Author information
Abstract
Ebola virus (EBOV) remains one of the most lethal transmissible infections and is responsible for high fatality rates and substantial morbidity during sporadic outbreaks. With increasing human incursions into endemic regions and the reported possibility of airborne transmission, EBOV is a high-priority public health threat for which no preventive or therapeutic options are currently available. Recent studies have demonstrated that cocktails of monoclonal antibodies are effective at preventing morbidity and mortality in nonhuman primates (NHPs) when administered as a post-exposure prophylactic within 1 or 2 days of challenge. To test whether one of these cocktails (MB-003) demonstrates efficacy as a therapeutic (after the onset of symptoms), we challenged NHPs with EBOV and initiated treatment upon confirmation of infection according to a diagnostic protocol for U.S. Food and Drug Administration Emergency Use Authorization and observation of a documented fever. Of the treated animals, 43% survived challenge, whereas both the controls and all historical controls with the same challenge stock succumbed to infection. These results represent successful therapy of EBOV infection in NHPs.

http://www.ncbi.nlm.nih.gov/pubmed/23966302

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PostPosted: Mon Aug 04, 2014 11:22 am 
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Sci Transl Med 21 August 2013:
Vol. 5, Issue 199, p. 199ra113
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3006608
RESEARCH ARTICLE
EBOLA
Therapeutic Intervention of Ebola Virus Infection in Rhesus Macaques with the MB-003 Monoclonal Antibody Cocktail
James Pettitt1,*, Larry Zeitlin2,*,†, Do H. Kim2, Cara Working3, Joshua C. Johnson1, Ognian Bohorov2, Barry Bratcher3, Ernie Hiatt3, Steven D. Hume3, Ashley K. Johnson3, Josh Morton3, Michael H. Pauly2, Kevin J. Whaley2, Michael F. Ingram1, Ashley Zovanyi1, Megan Heinrich1, Ashley Piper1, Justine Zelko1 and Gene G. Olinger1,†
+ Author Affiliations

1Division of Virology, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD 21702, USA.
2Mapp Biopharmaceutical Inc., 6160 Lusk Boulevard, #C105, San Diego, CA 92121, USA.
3Kentucky BioProcessing, LLC, 3700 Airpark Drive, Owensboro, KY 42301, USA.
+ Author Notes

↵* These authors contributed equally to this work.

↵†Corresponding author. E-mail: gene.olinger@us.army.mil (G.G.O.); larry.zeitlin@mappbio.com (L.Z.)
Abstract

Ebola virus (EBOV) remains one of the most lethal transmissible infections and is responsible for high fatality rates and substantial morbidity during sporadic outbreaks. With increasing human incursions into endemic regions and the reported possibility of airborne transmission, EBOV is a high-priority public health threat for which no preventive or therapeutic options are currently available. Recent studies have demonstrated that cocktails of monoclonal antibodies are effective at preventing morbidity and mortality in nonhuman primates (NHPs) when administered as a post-exposure prophylactic within 1 or 2 days of challenge. To test whether one of these cocktails (MB-003) demonstrates efficacy as a therapeutic (after the onset of symptoms), we challenged NHPs with EBOV and initiated treatment upon confirmation of infection according to a diagnostic protocol for U.S. Food and Drug Administration Emergency Use Authorization and observation of a documented fever. Of the treated animals, 43% survived challenge, whereas both the controls and all historical controls with the same challenge stock succumbed to infection. These results represent successful therapy of EBOV infection in NHPs.

Copyright © 2013, American Association for the Advancement of Science
Citation: J. Pettitt, L. Zeitlin, D. H. Kim, C. Working, J. C. Johnson, O. Bohorov, B. Bratcher, E. Hiatt, S. D. Hume, A. K. Johnson, J. Morton, M. H. Pauly, K. J. Whaley, M. F. Ingram, A. Zovanyi, M. Heinrich, A. Piper, J. Zelko, G. G. Olinger, Therapeutic Intervention of Ebola Virus Infection in Rhesus Macaques with the MB-003 Monoclonal Antibody Cocktail. Sci. Transl. Med. 5, 199ra113 (2013).

http://stm.sciencemag.org/content/5/199/199ra113.short

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PostPosted: Mon Aug 04, 2014 11:35 am 
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Consortium Led by Scripps Research Institute Scientist Wins Up to $28 Million from NIH to Find Best Proposed Ebola Treatment

LA JOLLA, CA – March 20, 2014 – The National Institutes of Health (NIH) has awarded a five-year grant of up to $28 million to establish a new center for excellence to find an antibody “cocktail” to fight the deadly Ebola virus. The project, which involves researchers from 15 institutions, will be led by Erica Ollmann Saphire, professor at The Scripps Research Institute (TSRI).

“It’s a global collaboration,” said Saphire. “Everyone in the field got on the same page to collaborate on a set of definitive experiments.”

Ebola virus causes an extremely virulent disease that leads to death in 25 to 90 percent of cases. Outbreaks of the fast-moving virus, which spreads via the blood or other bodily fluids of an infected person, have occurred in Uganda and the Democratic Republic of Congo in recent years.

For decades, scientists thought no antibodies were effective against Ebola virus, but in 2012, research from the U.S. Army Medical Research Institute of Infectious Diseases showed that a mix of antibodies can stop the virus. Other labs around the world were simultaneously testing other such antibody cocktails with success.

Today, a whole menu of antibodies have been identified as potentially therapeutic, and researchers are eager to figure out which combinations are most effective and why. Antibodies are currently thought to be the best strategy for treating rare and deadly viruses such as Ebola because they are effective even a couple of days after exposure, a time period during which a person could be airlifted to a hospital for treatment.

With $2.5 million of the grant going to Saphire’s laboratory, her team will use a technique called X-ray crystallography to study the structure of the antibodies and how they bind to the virus.

“The structures will provide an essential map for understanding how these antibodies work,” Saphire said. “If we understood why some are more effective than others, and which groupings gave better synergy, we could put together a better cocktail.”

One unique aspect of this program is that nearly everyone in the field is contributing antibodies. “It will not be this lab’s cocktail versus that lab’s cocktail,” Saphire said, “but an agreement, based upon a blinded study, that what we’ve put together is the best treatment possible from what is available in the world.”

Funding from the grant will also go to TSRI Assistant Professor Andrew Ward for studies using electron microscopy, a different technique for studying molecular structures. TSRI Professor Dennis Burton will contribute antibodies for the study.

Another part of the program is to develop antibody cocktails to fight other hemorrhagic fever viruses such as Marburg, Sudan and Lassa viruses.

The other institutions and scientists on the NIH National Institute of Allergy and Infectious Diseases (NIAID) Centers for Excellence in Translational Research (CETR) program grant, number U19AI109762, include Gary Kobinger at Public Health Agency of Canada, John Dye at U.S. Army Medical Research Institute of Infectious Diseases, Kartik Chandran and Jonathan Lai at Albert Einstein College of Medicine of Yeshiva University, Leslie Lobel at Ben Gurion University, Julius Lutwama at Uganda Virus Research Institute, Robert Garry and James Robinson at Tulane University, Thomas Geisbert at University of Texas Medical Branch, Yoshihiro Kawaoka at University of Wisconsin–Madison and Gene Olinger at NIAID. Biopharmaceutical companies on the grant include Mapp Biopharmaceutical (Larry Zeitlin), Zalgen labs (Luis Branco) and Cangene (Cory Nykiforuk).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

# # #

For information:
Office of Communications
Tel: 858-784-2666
Fax: 858-784-8136
press@scripps.edu

http://www.scripps.edu/news/press/2014/ ... phire.html

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PostPosted: Mon Aug 04, 2014 5:37 pm 
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niman wrote:
Sci Transl Med 21 August 2013:
Vol. 5, Issue 199, p. 199ra113
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3006608
RESEARCH ARTICLE
EBOLA
Therapeutic Intervention of Ebola Virus Infection in Rhesus Macaques with the MB-003 Monoclonal Antibody Cocktail
James Pettitt1,*, Larry Zeitlin2,*,†, Do H. Kim2, Cara Working3, Joshua C. Johnson1, Ognian Bohorov2, Barry Bratcher3, Ernie Hiatt3, Steven D. Hume3, Ashley K. Johnson3, Josh Morton3, Michael H. Pauly2, Kevin J. Whaley2, Michael F. Ingram1, Ashley Zovanyi1, Megan Heinrich1, Ashley Piper1, Justine Zelko1 and Gene G. Olinger1,†
+ Author Affiliations

1Division of Virology, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, MD 21702, USA.
2Mapp Biopharmaceutical Inc., 6160 Lusk Boulevard, #C105, San Diego, CA 92121, USA.
3Kentucky BioProcessing, LLC, 3700 Airpark Drive, Owensboro, KY 42301, USA.
+ Author Notes

↵* These authors contributed equally to this work.

↵†Corresponding author. E-mail: gene.olinger@us.army.mil (G.G.O.); larry.zeitlin@mappbio.com (L.Z.)
Abstract

Ebola virus (EBOV) remains one of the most lethal transmissible infections and is responsible for high fatality rates and substantial morbidity during sporadic outbreaks. With increasing human incursions into endemic regions and the reported possibility of airborne transmission, EBOV is a high-priority public health threat for which no preventive or therapeutic options are currently available. Recent studies have demonstrated that cocktails of monoclonal antibodies are effective at preventing morbidity and mortality in nonhuman primates (NHPs) when administered as a post-exposure prophylactic within 1 or 2 days of challenge. To test whether one of these cocktails (MB-003) demonstrates efficacy as a therapeutic (after the onset of symptoms), we challenged NHPs with EBOV and initiated treatment upon confirmation of infection according to a diagnostic protocol for U.S. Food and Drug Administration Emergency Use Authorization and observation of a documented fever. Of the treated animals, 43% survived challenge, whereas both the controls and all historical controls with the same challenge stock succumbed to infection. These results represent successful therapy of EBOV infection in NHPs.

Copyright © 2013, American Association for the Advancement of Science
Citation: J. Pettitt, L. Zeitlin, D. H. Kim, C. Working, J. C. Johnson, O. Bohorov, B. Bratcher, E. Hiatt, S. D. Hume, A. K. Johnson, J. Morton, M. H. Pauly, K. J. Whaley, M. F. Ingram, A. Zovanyi, M. Heinrich, A. Piper, J. Zelko, G. G. Olinger, Therapeutic Intervention of Ebola Virus Infection in Rhesus Macaques with the MB-003 Monoclonal Antibody Cocktail. Sci. Transl. Med. 5, 199ra113 (2013).

http://stm.sciencemag.org/content/5/199/199ra113.short

Therefore, we optimized a treatment protocol with three of eight EBOV glycoprotein (GP)–specific mAbs (1H3, 2G4, and 4G7) that were previously generated from mice vaccinated with the VSVΔG/EBOV-GP vaccine (23, 24). In enzyme-linked immunosorbent assays (ELISAs), mAb 2G4 bound to GP2, and 4G7 bound to epitopes in the C-terminal portion of GP1 of the EBOV-GP, whereas 1H3 bound to the soluble GP (sGP) portion (amino acids 1 to 295) (23). None of these EBOV-GP–specific mAbs are cross-reactive with Marburg virus or other EBOV species but did react with other EBOV strains. Individually, these antibodies protected mice and were more efficacious when administered 24 or 48 hours after the infection than at 1 to 4 days before infection. Although individually the antibodies were less protective in guinea pigs, a combination of the three neutralizing antibodies (1H3 + 2G4 + 4G7: 15 mg/kg combined total) was fully protective when administered on day 2 after infection (24).

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PostPosted: Mon Aug 04, 2014 5:44 pm 
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Escape mutations in ZMAb-treated nonsurvivors
To identify whether the two 48-hour–treated nonsurvivors were not protected by the ZMAb treatment because of escape mutations, we extracted the EBOV virus RNA from blood on day 8 for B2 and day 11 for B3 and subjected it to sequence analysis. The sequences were compared with the challenge virus sequence. Two mutations were found in EBOV isolated from B2 and were located at amino acids 275 and 508 of EBOV-GP (Fig. 6). These mutations were not found in any other natural EBOV isolates when searching GenBank. On the other hand, B3 did not have any escape mutants. B3 was euthanized on day 11 for humane reasons because of hindlimb paralysis. However, the clinical score for B3 was improving at this time because the subject was beginning to eat more and the fever was declining

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PostPosted: Mon Aug 04, 2014 5:53 pm 
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The present study demonstrates that administration of a combination of three neutralizing mAbs directed against the EBOV-GP can provide 100% or 50% protection when given 24 or 48 hours after exposure, respectively. The treatment resulted in lower virus loads, mild symptoms, and no shedding. The fact that the survivors demonstrated mainly normal blood biochemistry and hematology points out the effectiveness of the ZMAb treatment in preventing morbidity, which is also a desired feature of any therapeutic intervention. Additionally, the subjects were able to mount a noticeable EBOV-GP–specific humoral and cell-mediated immune response. The CD8+ response was generally broad, but predominantly against peptide pool 3, which spans amino acids 348 to 495 of EBOV-GP. The CD4+ response was also broad yet somewhat equivalent for all of the peptide pools. This is not surprising because the NHPs are outbred. Indeed, it is possible that the ZMAb treatment reduced EBOV replication long enough for an immune response to develop.

Overall, a 100% survival rate when starting treatment as late as 24 hours is 24-fold better than the current therapies that initiate treatment within 1 hour. The ability to achieve 50% protection when treatment starts at 48 hours after infection suggests that ZMAb delivered in this time period may also be a viable treatment option. Aside from an accidental laboratory infection, the administration of a life-saving treatment is likely to take place several hours if not days rather than minutes after infection. Rhesus macaques, which have a delayed time to death more in line with human infections, may further improve the percent survival in the 48-hour treatment group. Therefore, the capacity to improve survival by initiating treatment as late as 48 hours is a substantial advance over currently published protocols.

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