ZMapp

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Schematic representation of how monoclonal antibodies are generally made from hybridomas. To make ZMapp, the genes encoding for the antibodies were extracted from the hybridomas, genetically engineered to replace mouse components with human components, and transfected into tobacco plants. Monoclonals.png
Schematic representation of how monoclonal antibodies are generally made from hybridomas. To make ZMapp, the genes encoding for the antibodies were extracted from the hybridomas, genetically engineered to replace mouse components with human components, and transfected into tobacco plants.

ZMapp is an experimental biopharmaceutical medication comprising three chimeric monoclonal antibodies under development as a treatment for Ebola virus disease. [1] Two of the three components were originally developed at the Public Health Agency of Canada's National Microbiology Laboratory (NML), and the third at the U.S. Army Medical Research Institute of Infectious Diseases; the cocktail was optimized by Gary Kobinger, a research scientist at the NML [2] and underwent further development under license by Mapp Biopharmaceutical. ZMapp was first used on humans during the Western African Ebola virus epidemic, having only been previously tested on animals and not yet subjected to a randomized controlled trial. [3] The National Institutes of Health (NIH) ran a clinical trial starting in January 2015 with subjects from Sierra Leone, Guinea, and Liberia aiming to enroll 200 people, but the epidemic waned and the trial closed early, leaving it too statistically underpowered to give a meaningful result about whether ZMapp worked. [4]

Contents

In 2016, a clinical study comparing ZMapp to the current standard of care for Ebola was inconclusive. [5]

Chemistry

The drug is composed of three monoclonal antibodies (mAbs), initially harvested from mice exposed to Ebola virus proteins, that have been chimerized with human constant regions. [6] The components are chimeric monoclonal antibody c13C6 from a previously existing antibody cocktail called "MB-003" and two chimeric mAbs from a different antibody cocktail called ZMab, c2G4, and c4G7. [7] ZMapp is manufactured in the tobacco plant Nicotiana benthamiana in the bioproduction process known as "pharming" by Kentucky BioProcessing, a subsidiary of Reynolds American. [1] [8] [9]

Mechanism of action

Like intravenous immunoglobulin therapy, ZMapp contains a mixture of neutralizing antibodies that confer passive immunity to an individual, enhancing the normal immune response, and is designed to be administered after exposure to the Ebola virus. [10] Such antibodies have been used in the treatment and prevention of various infectious diseases and are intended to attack the virus by interfering with its surface and neutralizing it to prevent further damage. [10] [11]

The Nicotiana benthamiana tobacco plant Agroinfiltration.jpg
The Nicotiana benthamiana tobacco plant

History

Two of the drug's three components were originally developed at the Public Health Agency of Canada's National Microbiology Laboratory (NML), and a third at the U.S. Army Medical Research Institute of Infectious Diseases; [2] the cocktail was optimized by Gary Kobinger, then branch chief of the NML, and is undergoing further development by Leaf Biopharmaceutical (LeafBio, Inc.), a San Diego–based arm of Mapp Biopharmaceutical. [12] LeafBio created ZMapp in collaboration with its parent and Defyrus Inc., each of which had licensed its own cocktail of antibodies, called MB-003 and ZMab. [13] [ citation needed ]

MB-003

MB-003 is a cocktail of three humanized or human–mouse chimeric mAbs: c13C6, h13F6, and c6D8. [7] A study published in September 2012 found that rhesus macaques infected with Ebola virus (EBOV) survived when receiving MB-003 (mixture of 3 chimeric monoclonal antibodies) one hour after infection. When treated 24 or 48 hours after infection, four of six animals survived and had little to no viremia and few, if any, clinical symptoms. [14]

MB-003 was created by scientists at the U.S. Army Medical Research Institute of Infectious Diseases, Gene Olinger, and Jamie Pettitt in collaboration with Mapp Biopharmaceutical with years of funding from US government agencies including the National Institute of Allergy and Infectious Disease, Biomedical Advanced Research and Development Authority, and the Defense Threat Reduction Agency. [1] [2] [15]

ZMAb

ZMAb is a mixture of three mouse mAbs: m1H3, m2G4, and m4G7. [7] A study published in November 2013 found that EBOV-infected macaque monkeys survived after being given a therapy with a combination of three EBOV surface glycoprotein (EBOV-GP)-specific monoclonal antibodies (ZMAb) within 24 hours of infection. The authors concluded that post-exposure treatment resulted in a robust immune response, with good protection for up to 10 weeks and some protection at 13 weeks. [16] ZMab was created by the NML and licensed to Defyrus, a Toronto-based biodefense company, with further funding by the Public Health Agency of Canada. [2]

ZMapp

A 2014 paper described how Mapp and its collaborators, including investigators at Public Health Agency of Canada, Kentucky BioProcessing, and the National Institute of Allergy and Infectious Diseases, first chimerized the three antibodies comprising ZMAb, then tested combinations of MB-003 and the chimeric ZMAb antibodies in guinea pigs and then primates to determine the best combination, which turned out to be c13C6 from MB-003 and two chimeric mAbs from ZMAb, c2G4 and c4G7. This is ZMapp. [7]

In an experiment also published in the 2014 paper, 21 rhesus macaque primates were infected with the Kikwit Congolese variant of EBOV. Three primates in the control arm were given a non-functional antibody, and the 18 in the treatment arm were divided into three groups of six. All primates in the treatment arm received three doses of ZMapp, spaced 3 days apart. The first treatment group received its first dose on 3rd day after being infected; the second group on the 4th day after being infected, and the third group, on the 5th day after being infected. All three primates in the control group died; all 18 primates in the treatment arm survived. [7] Mapp then went on to show that ZMapp inhibits replication of a Guinean strain of EBOV in cell cultures. [17]

Mapp remains involved in the production of the drug through its contracts with Kentucky BioProcessing, a subsidiary of Reynolds American. [1] To produce the drug, genes coding for the chimeric mAbs were inserted into viral vectors, and tobacco plants are infected with the viral vector encoding for the antibodies, using Agrobacterium cultures. [18] [19] [20] Subsequently, antibodies are extracted and purified from the plants. Once the genes encoding the chimeric mAbs are in hand, the entire tobacco production cycle is believed to take a few months. [3] The development of these production methods was funded by the U.S. Defense Advanced Research Projects Agency as part of its bio-defense efforts following the 9/11 terrorist attacks. [21] [22]

Use during the 2014–2016 Ebola outbreak in West Africa

ZMapp was first used during the 2014 West Africa Ebola Virus outbreak, having not previously undergone any human clinical trials to determine its efficacy or potential risks. [3] By October 2014, the United States Food and Drug Administration had approved the use of several experimental drugs, including ZMapp, to be used on patients infected with Ebola virus. The use of such drugs during the epidemic was also deemed ethical by the World Health Organization (WHO). [23] In 2014, a limited supply of ZMapp was used to treat 7 individuals infected with the Ebola virus; of these 2 died. [24] [25] The outcome is not considered to be statistically significant. Mapp announced in August 2014, that supplies of ZMapp had been exhausted. [26]

Controversy

The lack of drugs and unavailability of experimental treatment in the most affected regions of the West African Ebola virus outbreak spurred some controversy. [3] The fact that the drug was first given to Americans and a European and not to Africans, according to the Los Angeles Times , "provoked outrage, feeding into African perceptions of Western insensitivity and arrogance, with a deep sense of mistrust and betrayal still lingering over the exploitation and abuses of the colonial era". [27] Salim S. Abdool Karim, the director of an AIDS research center in South Africa, placed the issue in the context of the history of exploitation and abuses. Responding to a question on how people might have reacted if ZMapp and other drugs had first been used on Africans, he said "It would have been the front-page screaming headline: 'Africans used as guinea pigs for American drug company's medicine'". [3]

In August 2014, the World Health Organization called for convening a panel of medical authorities "to consider whether experimental drugs should be more widely released." In a statement, Peter Piot (co-discoverer of the Ebola virus); Jeremy Farrar, the director of the Wellcome Trust; and David Heymann of the Chatham House Center on Global Health Security, called for the release of experimental drugs for the 2014 West Africa Ebola outbreak. [27]

At an August 2014 press conference, Barack Obama, the President of the United States, was questioned regarding whether the cocktail should be fast-tracked for approval or be made available to sick patients outside of the United States. He responded, "I think we've got to let the science guide us. I don't think all the information's in on whether this drug is helpful." [28]

Clinical trial

The National Institutes of Health announced on 27 February 2015 the commencement of a randomized controlled trial of ZMapp to be conducted in Liberia and the United States. [29] From March 2015 through November 2015, 72 individuals infected with the Ebola virus were enrolled in the trial; investigators stopped enrolling new subjects in January 2016, having failed to reach its enrollment goal of 200 due to the waning of the Ebola outbreak. As a result, although a 40% lower risk of death was calculated for those who received ZMapp, the difference was not statistically significant and ultimately it could not be determined whether the use of ZMapp was superior to the optimized standard of care alone. However, ZMapp was found to be safe and well tolerated. [4] [30] [31]

Use during the 2018-19 Kivu Ebola outbreak in the Democratic Republic of the Congo

The ZMapp cocktail was assessed by the World Health Organization for emergency use under the Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI) ethical protocol. The panel agreed that "the benefits of ZMapp outweigh its risks" while noting that it presented logistical challenges, particularly that of requiring a cold chain for distribution and storage. [32] Four alternative therapies (remdesivir, the Regeneron product atoltivimab/maftivimab/odesivimab, favipiravir, and ansuvimab) were also considered for use, but they were at earlier stages of development. [32] In August 2019, the Democratic Republic of the Congo's national health authorities, the World Health Organization, and the National Institutes of Health announced that they would stop using ZMapp, along with all other Ebola treatments except atoltivimab/maftivimab/odesivimab and ansuvimab, in their ongoing clinical trials, citing the higher mortality rates of patients not treated with atoltivimab/maftivimab/odesivimab and ansuvimab. [33] [34]

In October 2020, the US Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab with an indication for the treatment of infection caused by Zaire ebolavirus. [35]

Related Research Articles

In immunology, antiserum is a blood serum containing antibodies that is used to spread passive immunity to many diseases via blood donation (plasmapheresis). For example, convalescent serum, passive antibody transfusion from a previous human survivor, used to be the only known effective treatment for ebola infection with a high success rate of 7 out of 8 patients surviving.

<i>Ebolavirus</i> Genus of virus

The genus Ebolavirus is a virological taxon included in the family Filoviridae, order Mononegavirales. The members of this genus are called ebolaviruses, and encode their genome in the form of single-stranded negative-sense RNA. The six known virus species are named for the region where each was originally identified: Bundibugyo ebolavirus, Reston ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus, Zaire ebolavirus, and Bombali ebolavirus. The last is the most recent species to be named and was isolated from Angolan free-tailed bats in Sierra Leone. Each species of the genus Ebolavirus has one member virus, and four of these cause Ebola virus disease (EVD) in humans, a type of hemorrhagic fever having a very high case fatality rate. The Reston virus has caused EVD in other primates. Zaire ebolavirus has the highest mortality rate of the ebolaviruses and is responsible for the largest number of outbreaks of the six known species of the genus, including the 1976 Zaire outbreak and the outbreak with the most deaths (2014).

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The Vaccine Research Center (VRC), is an intramural division of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), US Department of Health and Human Services (HHS). The mission of the VRC is to discover and develop both vaccines and antibody-based products that target infectious diseases.

A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy.

<span class="mw-page-title-main">Marburg virus</span> Species of filamentous virus responsible for hemorrhagic fever

Marburg virus (MARV) is a hemorrhagic fever virus of the Filoviridae family of viruses and a member of the species Marburg marburgvirus, genus Marburgvirus. It causes Marburg virus disease in primates, a form of viral hemorrhagic fever. The World Health Organization (WHO) rates it as a Risk Group 4 Pathogen. In the United States, the National Institute of Allergy and Infectious Diseases ranks it as a Category A Priority Pathogen and the Centers for Disease Control and Prevention lists it as a Category A Bioterrorism Agent. It is also listed as a biological agent for export control by the Australia Group.

<span class="mw-page-title-main">Ebola</span> Viral hemorrhagic fever of humans and other primates caused by ebolaviruses

Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after infection. The first symptoms are usually fever, sore throat, muscle pain, and headaches. These are usually followed by vomiting, diarrhoea, rash and decreased liver and kidney function, at which point some people begin to bleed both internally and externally. It kills between 25% and 90% of those infected – about 50% on average. Death is often due to shock from fluid loss, and typically occurs between six and 16 days after the first symptoms appear. Early treatment of symptoms increases the survival rate considerably compared to late start. An Ebola vaccine was approved by the US FDA in December 2019.

Mapp Biopharmaceutical is an American pharmaceutical company founded in 2003 by Larry Zeitlin and Kevin Whaley. Mapp Biopharmaceutical is based in San Diego, California. It is responsible for the research and development of ZMapp, a drug which is still under development and comprises three humanized monoclonal antibodies used as a treatment for Ebola virus disease. The drug was first tested in humans during the 2014 West Africa Ebola virus outbreak.

TKM-Ebola was an experimental antiviral drug for Ebola disease that was developed by Arbutus Biopharma in Vancouver, Canada. The drug candidate was formerly known as Ebola-SNALP.

<span class="mw-page-title-main">Ebola vaccine</span> Vaccine against Ebola

Ebola vaccines are vaccines either approved or in development to prevent Ebola. As of 2022, there are only vaccines against the Zaire ebolavirus. The first vaccine to be approved in the United States was rVSV-ZEBOV in December 2019. It had been used extensively in the Kivu Ebola epidemic under a compassionate use protocol. During the early 21st century, several vaccine candidates displayed efficacy to protect nonhuman primates against lethal infection.

<span class="mw-page-title-main">Galidesivir</span> Antiviral drug

Galidesivir is an antiviral drug, an adenosine analog. It was developed by BioCryst Pharmaceuticals with funding from NIAID, originally intended as a treatment for hepatitis C, but subsequently developed as a potential treatment for deadly filovirus infections such as Ebola virus disease and Marburg virus disease, as well as Zika virus. Currently, galidesivir is under phase 1 human trial in Brazil for coronavirus.

cAd3-ZEBOV Experimental vaccine for ebolaviruses

cAd3-ZEBOV was an experimental vaccine for two ebolaviruses, Ebola virus and Sudan virus, developed by scientists at GlaxoSmithKline (GSK) and tested by National Institute of Allergy and Infectious Disease (NIAID). This vaccine is derived from a chimpanzee adenovirus, Chimp Adenovirus type 3 (ChAd3), genetically engineered to express glycoproteins from the Zaire and Sudan species of ebolavirus to provoke an immune response against them. Simultaneous phase 1 trials of this vaccine commenced in September 2014, being administered to volunteers in Oxford and Bethesda. During October the vaccine is being administered to a further group of volunteers in Mali. If this phase is completed successfully, the vaccine will be fast tracked for use in the Ebola virus epidemic in West Africa. In preparation for this, GSK is preparing a stockpile of 10,000 doses.

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<span class="mw-page-title-main">2018 Équateur province Ebola outbreak</span> Disease outbreak in the Democratic Republic of the Congo

The 2018 Équateur province Ebola outbreak occurred in the north-west of the Democratic Republic of the Congo (DRC) from May to July 2018. It was contained entirely within Équateur province, and was the first time that vaccination with the rVSV-ZEBOV Ebola vaccine had been attempted in the early stages of an Ebola outbreak, with a total of 3,481 people vaccinated. It was the ninth recorded Ebola outbreak in the DRC.

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Atoltivimab is a Zaire ebolavirus glycoprotein-directed human monoclonal antibody that is part of the fixed-dose combination atoltivimab/maftivimab/odesivimab that is used for the treatment of Zaire ebolavirus.

Odesivimab is a Zaire ebolavirus glycoprotein-directed human monoclonal antibody that is part of the fixed-dose combination atoltivimab/maftivimab/odesivimab that is used for the treatment of Zaire ebolavirus.

Gary P. Kobinger is a Canadian immunologist and virologist who is currently the director at the Galveston National Laboratory at the University of Texas. He has held previous professorships at Université Laval, the University of Manitoba, and the University of Pennsylvania. Additionally, he was the chief of the Special Pathogens Unit at the National Microbiology Laboratory (NML) of the Public Health Agency of Canada (PHAC) in Winnipeg, Manitoba, for eight years. Kobinger is known for his critical role in the development of both an effective Ebola vaccine and treatment. His work focuses on the development and evaluation of new vaccine platforms and immunological treatments against emerging and re-emerging viruses that are dangerous to human health.

Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

References

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  32. 1 2 "Notes for the record: Consultation on Monitored Emergency Use of Unregistered and Investigational Interventions for Ebola Virus Disease (EVD)" (PDF). World Health Organization (WHO). 17 May 2018. Retrieved 25 May 2018.
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