A new report out of College Station, Texas notes that if the need for mass production of an experimental Ebola drug is needed to combat an epidemic outbreak in the United States, Texas A&M University could serve as a mass-production center for the therapy.
The news comes on the heels of a developing story surrounding two seriously ill American medical missionaries, Dr. Kent Brantly of the Samaritan’s Purse non-denominational evangelical Christian International Relief organization based in Boone North Carolina, and Nancy Writebol — an aid worker also from North Carolina who works with Serving in Mission (SIM) — were flown this week to Atlanta on a private jet fitted with an isolation chamber, and transferred under heavy security to the Emory University hospital’s special isolation unit for treatment. The two Americans became infected with highly-lethal Ebola while working at a treatment center in Liberia — one of the West African nations hit hardest by the worst Ebola outbreak on record. Dr. Brantly and Ms. Writebol have both volunteered to be treated with an unlicensed experimental drug called ZMapp, a product of Mapp Biopharmaceutical of San Diego, in collaboration with San Diego based Leaf Biopharmaceutical Inc.
In July, Toronto, Canada-based Defyrus, a private, life sciences biodefense 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, announced an exclusive, worldwide license to their Ebola therapeutic monoclonal antibody (mAb) patent portfolio to Leaf Biopharmaceutical. The license expands the commercial relationship between LeafBio and Defyrus, which 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 — ZMab — which is composed of the best mAbs of MB-003 and ZMapp.
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 clinical development program has been welcomed by our US government partners,” commented 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 of Owensboro, Kentucky. 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.
Currently there are no available vaccines or treatments approved for use in humans infected with the Ebola virus (formerly known as Ebola Haemorragic Fever) and until now, ZMapp had not been tested on human subjects.
Ebola virus has human case fatality rates as high as 90 percent, and is responsible for some 1,800 cases and nearly 1,000 deaths in the current West African outbreak affecting Guinea, Sierra Leone, Liberia, and the latest — Nigeria, over the past several months. In addition to being a global health concern, the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) also considers Ebola a potential biological threat agent.
A joint statement from Mapp Biopharmaceutical and LeafBio describes ZMapp as the result of a collaboration between Mapp Biopharmaceutical, Inc., LeafBio, Defyrus Inc., the U.S. government, and the Public Health Agency of Canada (PHAC). The drug is composed of three humanized monoclonal antibodies manufactured in plants, specifically Nicotiana, and is an optimized cocktail combining the best components of MB-003 (Mapp) and ZMAb (Defyrus/PHAC).
The companies caution that ZMapp was first identified as a drug candidate in January 2014, and has not yet been evaluated for safety in humans. As such, very little of the drug is currently available, and any decision to use it as an experimental drug in a patient would be a decision made by the treating physician under the regulatory guidelines of the FDA. Mapp and its partners are cooperating with appropriate government agencies to increase production as quickly as possible.
Texas A&M Could Mass-Produce ZMapp If Needed
The Bryan/College Station Eagle‘s Emily Wilkins reports in her article, “Texas A&M could be in the running to mass-produce Ebola treatment,” that if the treatment is successful, ZMapp could be mass-produced at the Texas A&M Center for Innovation in Advanced Development and Manufacturing, which is one of just three facilities in America equipped to standardize a treatment for a virus such as Ebola, according to Dr. Scott R. Lillibridge, a professor of epidemiology and assistant dean with the Texas A&M Health Science Center School of Rural Public Health in Houston.
Dr. Lillibridge previously served with the Department of Health and Human Services (HHS) as special assistant to the HHS Secretary for National Security and Emergency Management, and assisted in development of a national preparedness program when the nation was experiencing anthrax attacks in 2001. Dr. Lillibridge was also the founding director of the Bioterrorism Preparedness and Response Program at the Centers for Disease Control and Prevention (CDC). In addition to infectious disease concerns, this office provided program support for the development of a national pharmaceutical stockpile, enhanced disease tracking, training and national laboratory enhancement that provided funding for preparedness to every state and territorial health department throughout the United States.
Dr. Lillibridge’s career at CDC focused on emergency public health response issues. He has worked in emergency response and preparedness roles throughout the world in support of the U.S. government and non-governmental organizations. He was the lead physician during the initial U.S. Public Health Service (PHS) response to the Oklahoma City bombing and also led the U.S. Medical Delegation to Tokyo following the sarin release in 1995. In 2003, Dr. Lillibridge was summoned to China to consult with the Ministry of Health during the SARS epidemic. He also served on the UN Interagency Rapid Health Assessment Team led by the World Health Organization (WHO) that responded to the Indian Ocean tsunami in Indonesia.
Animal Study Results With ZMapp (MB-003) Promising
An Ebola virus study resulting from a widespread scientific collaboration has shown promising preliminary results, preventing disease in infected nonhuman primates using monoclonal antibodies.
In an article published in the online edition of the Proceedings of the National Academy of Sciences (PNAS), the study research team describes a proof-of-concept for using a “cocktail” of monoclonal antibodies, or mAbs, to prevent lethal disease in rhesus macaques. When administered one hour after infection, all animals survived. Two-thirds of the animals were protected even when the treatment, known as MB-003, was administered 48 hours after infection.
The work is culmination of more than a decade of effort between government and industry partners. According to lead investigator Gene Olinger, Ph.D., a virologist at USAMRIID, the consortium of investigators took very distinct technologies and combined them to develop a cutting-edge medical countermeasure against a lethal viral disease.
“It is rare that an antiviral compound prevents Ebola virus infection with limited to no morbidity in treated animals at any point of treatment following infection by this lethal virus,” comments Dr. Olinger in a USAMRIID release. “Until recently, attempts to utilize antibodies to provide protection against Ebola virus have been met with failure. The level of protection against disease that we saw with MB-003 was impressive.”
In the PNAS report, entitled “Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques” (PNAS vol. 109 no. 44 Gene Garrard Olinger, Jr., 18030–18035, dpi: 10.1073/pnas.1213709109), the researchers note that filovirus infections can cause a severe and often fatal disease in humans and nonhuman primates, including great apes, and that in this study, three anti-Ebola virus mouse/human chimeric mAbs (c13C6, h-13F6, and c6D8) were produced in Chinese hamster ovary and in whole plant (Nicotiana benthamiana) cells. They report that in pilot experiments testing a mixture of the three mAbs (MB-003), they found that MB-003 produced in both manufacturing systems protected rhesus macaques from lethal challenge when administered 1 h postinfection. In a pivotal follow-up experiment, they also found significant protection (P < 0.05) when MB-003 treatment began 24 or 48 h postinfection (four of six survived vs. zero of two controls).
The scientists report that in all experiments, surviving animals that received MB-003 experienced little to no viremia and had few, if any, of the clinical symptoms observed in the controls, and conclude that the results represent successful post exposure in vivo efficacy by a mAb mixture and suggest that this immunoprotectant should be further pursued as a post exposure and potential therapeutic for Ebola virus exposure.
But Dr. Neil Rau, an Ontario, Canada-based infectious disease consultant, commented to CTV News that while the ZMapp treatment shows promise. Researchers will still have to perform controlled trials of the drug with a larger group of patients than just Dr. Brantly and Ms. Writebol. “Although this is a very promising story, having one patient receive it and having a good outcome is not the same as a clinical trial,” Dr.Rau noted, “I would be a little cautious about hailing this as the ‘magic bullet,’ but it’s very interesting.”
“We were pleased to see how well the humanized mAbs of MB-003 performed,” commented Larry Zeitlin, Ph.D., president of Mapp Biopharmaceutical and senior author on the study. “We also were pleasantly surprised by the superiority of the plant-derived mAbs compared to the same mAbs produced in traditional mammalian cell culture.”
As noted above, the drug is cultured in tobacco plants genetically engineered to produce the monoclonal antibodies by Kentucky BioProcessing, a subsidiary of the major tobacco firm Reynolds American.
Kentucky BioProcessing, which was acquired by Reynolds American in January, conducts contract research and development for Mapp Biopharmaceutical, according to David Howard, spokesman for Reynolds American subsidiary RAI Services. “In the last week, Kentucky BioProcessing complied with a request from Emory University and Samaritan’s Purse to provide a very limited amount (of the compound) to Emory, and KPB has done that,” Mr. Howard told the Lexington Herald-Leader’s Janet Patton.
Ms. Patton notes that In 2007, Mapp, working under contract for the U.S. Department of Defense and other federal agencies, engaged KBP to develop a process to manufacture a compound designed to be a post-exposure treatment for Ebola virus. That compound was MB-003 or ZMapp.
Canadian Press health reporter Helen Branswell notes that two of the ZMapp monoclonal antibodies are the product of years of research done at the Public Health Agency of Canada’s National Microbiology Laboratory in Winnipeg. The third was developed at the U.S. Army Medical Research Institute of Infectious Diseases. Ms. Branswell says the Winnipeg lab and other research facilities have been working for years to produce Ebola and Marburg virus interventions, but lack of funding and regulatory hurdles had prevented these experimental tools from being used to address actual outbreaks up until now. However, she says ZMapp is unlikely to change the course of the current outbreak in Africa, since only very small quantities of the drug are available, and ramping up production of a drug or a vaccine only happens when it has been licensed and the manufacturer is ready to take it to market.
The tobacco plant system is a new development process that significantly decreases the amount of time required for production, increases the quantity of antibody produced, and slashes the cost of manufacturing, according to Barry Bratcher, chief operating officer of KBP and a co-author on the PNAS study. “Our GMP facility can generate a new antibody lot in two weeks to rapidly address new threats and new outbreaks,” says Mr. Bratcher.
Dr. Olinger said efforts are underway to advance MB-003 to clinical safety testing as his team at USAMRIID continues to determine the true therapeutic capability of the cocktail.
The Texas A&M Center for Innovation in Advanced Development and Manufacturing is geared to accelerating research and development of vaccines and therapeutics, with the goal of shepherding these products through pre-clinical and clinical development to licensure and production as quickly as possible consistent with due diligence, in order to assure that necessary vaccines and countermeasures are available to the nation in the quantity needed, at the precise time of need, while assuring uncompromised safety and effectiveness.and prepared to rapidly produce these products in case of pandemics or other national emergencies.
In addition to meeting America’s’s biosecurity needs, this capability can also be utilized by academic and commercial scientists to facilitate development of new vaccines and biological drugs for diseases such as cancer and diabetes, as well as for globally significant infectious diseases like malaria, HIV/AIDS, and currently Ebola. The modular, flexible technologies implemented at the NCTM are ideal not only for expediting the pace of clinical research but also for enabling production of multiple products simultaneously within a single facility. The modular technology ensures that the production of all products are managed in self-contained environments, eliminating the potential for cross contamination.
The Center is the prime contractor for a cohesive team of leading academic, non-profit and commercial institutions that provide the Center’s personnel, infrastructure, products, intellectual property, and commitment to U.S.-based advanced development and manufacturing. It is founded on an initial $285.6 million public-private partnership with the U.S. Department of Health and Human Services designed to enhance the nation’s emergency preparedness by providing surge capacity for pandemic influenza vaccines and medical countermeasures to chemical, biological, radiological and nuclear threats.
Multiple agencies contributed funding for the research behind the ZMapp study and related studies, including the National Institutes of Health, the Defense Advanced Research Projects Agency, the Transformational Medical Technologies Initiative, and the Defense Threat Reduction Agency.
USAMRIID’s mission is to protect warfighters 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.
Texas A&M Center for Innovation in Advanced Development and Manufacturing
U.S. Army Medical Research Institute of Infectious Diseases
Leaf Biopharmaceutical Inc.
Proceedings of the National Academy of Sciences (PNAS)
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