MAb114

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mAb114 is a monoclonal antibody that is being evaluated as a treatment for Ebola virus disease. [1] Its discovery was led by the laboratory of Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and J. J. Muyembe-Tamfum from the Institut National pour la Recherche Biomedicale (INRB) in the Democratic Republic of Congo, working in collaboration with the Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases. [2] [3] mAb114 was isolated from the blood of a survivor of the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo roughly ten years later. [2]

Contents

In early 2018, a Phase 1 clinical trial of mAb114 was conducted by Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Julie E. Ledgerwood. [4] [5] [6] mAb114 is also being evaluated during the 2018 North Kivu Ebola outbreak. [7]

mAb114 has also shown success with lowering the mortality rate from ~70% to about 34%. In August 2019, Congolese health authorities, the World Health Organization, and the U.S. National Institutes of Health promoted the use of mAb114, alongside REGN-EB3, a similar Regeneron-produced monoclonal antibody treatment, over other treatments yielding higher mortality rates, after ending clinical trials during the outbreak. [8] [9]

Chemistry

The drug is composed of a single monoclonal antibody (mAb) and was initially isolated from immortalized B-cells that were obtained from a survivor of the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo. [2] In work supported by the United States National Institutes of Health and the Defense Advanced Projects Agency, the heavy and light chain sequences of mAb114 mAb was cloned into CHO cell lines and initial production runs were produced by Cook Phamica d.b.a. Catalent under contract of Medimmune. [5] [4]

Mechanism of action

Neutralization

mAb114 is a monoclonal antibody therapy that is infused intravenously into patients with Ebola virus disease. mAb114 is a neutralizing antibody, [2] meaning It binds to a protein on the surface of Ebola virus that is required to infect cells. Specifically, mAb114 neutralizes infection by binding to a region of the Ebola virus envelope glycoprotein that, in the absence of mAb114, would interact with virus's cell receptor protein, Niemann-Pick C1 (NPC1). [10] [11] [12] This "competition" by mAb114 prevents Ebola virus from binding to NPC1 and "neutralizes" the virus's ability to infect the targeted cell. [10]

Effector function

Antibodies have antigen-binding fragment (Fab) regions and constant fragment (Fc) regions. The Neutralization of virus infection occurs when the Fab regions of antibodies binds to virus antigen(s) in a manner that blocks infection. Antibodies are also able to "kill" virus particles directly and/or kill infected cells using antibody-mediated "effector functions" such as opsonization, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and antibody-dependent phagocytosis. These effector functions are contained in the Fc region of antibodies, but is also dependent on binding of the Fab region to antigen. Effector functions also require the use of complement proteins in serum or Fc-receptor on cell membranes. mAb114 has been found to be capable of killing cells by antibody-dependent cell-mediated cytotoxicity. [2] Other functional killing tests have not been performed.

History

Discovery

A 2016 paper describes the efforts of how mAb114 was originally developed as part of research efforts lead by Dr. Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and Dr. J. J. Muyembe-Tamfum from the Institut National de Recherche Biomedicale (INRB) in the Democratic Republic of Congo. [2] [3] This collaborative effort also involved researchers from Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases. [2] [3] A survivor from the 1995 outbreak of Ebola virus disease in Kikwit, Democratic Republic of Congo donated blood to the project that began roughly ten years after they had recovered. [2] Memory B cells isolated from the survivor's blood were immortalized, cultured and screened for their ability to produce monoclonal antibodies that reacted with the glycoprotein of Ebola virus. mAb114 was identified from one of these cultures and the antibody heavy and light chain gene sequences were sequenced from the cells. [2] These sequences were then cloned into recombinant DNA plasmids and purified antibody protein for initial studies was produced in cells derived from HEK 293 cells. [2]

mAb114 and mAb100 combination

In an experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and treated with a combination of mAb114 and another antibody isolated from the same subject, mAb100. Three doses of the combination were given once a day starting 1 day after the animals were infected. The control animal died and the treated animals all survived. [2]

mAb114 monotherapy

In a second experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and only treated with mAb114. Three doses of mAb114 were given once a day starting 1 day or 5 days after the animals were infected. The control animals died and the treated animals all survived. [2] Unpublished data referred to in a publication of the 2018 Phase I clinical trial results of mAb114, reported that a single infusion of mAb114 provided full protection of rhesus macaques and was the basis of the dosing used for human studies. [4] [5]

Development

mAb114 was developed by the Vaccine Research Center with support of the United States National Institutes of Health and the Defense Advanced Projects Agency. The heavy and light chain sequences of mAb114 mAb were cloned into CHO cell lines to enable large-scale production of antibody product for use in humans. [5] [4]

Human safety testing

In early 2018, [1] a Phase 1 clinical trial of mAb114's safety, tolerability and pharmacokinetics was conducted by Dr. Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Dr. Julie E. Ledgerwood. [4] [5] [6] The study was performed in the United States at the NIH Clinical Center and tested single dose infusions of mAb114 infused over 30 minutes. The study showed that mAb114 was safe, had minimal side effects and had a half-life of 24 days. [4] [5]

Ridgeback Biotherapeutics

A license for mAb114 was obtained by Ridgeback Biotherapeutics LP in 2018 from the National Institutes of Health-National Institute of Allergy and Infectious Diseases. [13] Ridgeback Biotherapeutics LP is a small biotechnology company that focuses on pediatric orphan and emerging infectious diseases. [14] mAb114 was given orphan drug status in May 2019. [15]

Experimental use in the Democratic Republic of Congo

During the 2018 Équateur province Ebola outbreak, mAb114 was requested by the Democratic Republic of Congo (DRC) Ministry of Public Health. mAb114 was approved for compassionate use by the World Health Organization MEURI ethical protocol and at DRC ethics board. mAb114 was sent along with other therapeutic agents to the outbreak sites. [16] [17] [6] However, the outbreak came to a conclusion before any therapeutic agents were given to patients. [6]

Approximately one month following the conclusion of the Équateur province outbreak, a distinct outbreak was noted in Kivu in the DRC (2018–20 Kivu Ebola outbreak). Once again, mAb114 received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols. [6] In November 2018, the Pamoja Tulinde Maisha (PALM [together save lives]) open-label randomized clinical control trial was begun at multiple treatment units testing mAb114, REGN-EB3 and remdesivir to ZMapp. Despite the difficulty of running a clinical trial in a conflict zone, investigators have enrolled 681 patients towards their goal of 725. An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that mAb114 and REGN-EB3 were superior to the comparator ZMapp. Overall mortality of patients in the ZMapp and remdesivir groups were 49% and 53% compared to 34% and 29% for mAb114 and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for mAB114 and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and mAb114, the survival difference between those two therapies and ZMapp was significant. This led to the DSMB halting the study and PALM investigators dropping the remdesivir and ZMapp arms from the clinical trial. All patients in the outbreak who elect to participate in the trial will now be given either mAb114 or REGN-EB3. [18] [19] [8] [7]

In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab (Inmazeb, formerly REGN-EB3) with an indication for the treatment of infection caused by Zaire ebolavirus. [20]

Related Research Articles

Viral hemorrhagic fever Type of illnesses

Viral hemorrhagic fevers (VHFs) are a diverse group of animal and human illnesses in which fever and hemorrhage are caused by a viral infection. VHFs may be caused by five distinct families of RNA viruses: the families Filoviridae, Flaviviridae, Rhabdoviridae, and several member families of the Bunyavirales order such as Arenaviridae, and Hantaviridae. All types of VHF are characterized by fever and bleeding disorders and all can progress to high fever, shock and death in many cases. Some of the VHF agents cause relatively mild illnesses, such as the Scandinavian nephropathia epidemica, while others, such as Ebola virus, can cause severe, life-threatening disease.

Crimean–Congo hemorrhagic fever Viral disease

Crimean–Congo hemorrhagic fever (CCHF) is a viral disease. Symptoms of CCHF may include fever, muscle pains, headache, vomiting, diarrhea, and bleeding into the skin. Onset of symptoms is less than two weeks following exposure. Complications may include liver failure. In those who survive, recovery generally occurs around two weeks after onset.

Regeneron Pharmaceuticals American biotechnology company

Regeneron Pharmaceuticals, Inc. is an American biotechnology company headquartered in Tarrytown, New York. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities, it branched out into the study of both cytokine and tyrosine kinase receptors.

Monoclonal antibody therapy Form of immunotherapy

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses. More recently antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.

Passive immunity is the transfer of active humoral immunity of ready-made antibodies. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and it can also be induced artificially, when high levels of antibodies specific to a pathogen or toxin are transferred to non-immune persons through blood products that contain antibodies, such as in immunoglobulin therapy or antiserum therapy. Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases. Passive immunization can be provided when people cannot synthesize antibodies, and when they have been exposed to a disease that they do not have immunity against.

Vaccine Research Center

The Dale and Betty Bumpers Vaccine Research Center, more commonly known as the Vaccine Research Center (VRC), is an Intramural Division of the National Institute of Allergy and Infectious Diseases, one of the US National Institutes of Health. The mission of the VRC is "to conduct research that facilitates the development of effective vaccines for human disease." The primary focus of research is the development of vaccines for AIDS, but the VRC also is working to develop vaccines for Ebola and the Marburg virus, and therapeutic antibodies against SARS-CoV2.

A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralisation renders the particle no longer infectious or pathogenic. Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, intracellular 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. Immunity due to neutralizing antibodies is also known as sterilizing immunity, as the immune system eliminates the infectious particle before any infection takes place.

Ebola Viral hemorrhagic fever of humans and other primates caused by ebolaviruses

Ebola, also known as Ebola virus disease (EVD) or Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever of humans and other primates caused by ebolaviruses. Signs and symptoms typically start between two days and three weeks after contracting the virus with a fever, sore throat, muscular pain, and headaches. Vomiting, diarrhoea and rash usually follow, along with decreased function of the liver and kidneys. At this time, some people begin to bleed both internally and externally. The disease has a high risk of death, killing 25% to 90% of those infected, with an average of about 50%. This is often due to low blood pressure from fluid loss, and typically follows six to 16 days after symptoms appear.

ZMapp Experimental treatment for Ebola virus disease

ZMapp is an experimental biopharmaceutical drug comprising three chimeric monoclonal antibodies under development as a treatment for Ebola virus disease. 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 and underwent further development under license by Mapp Biopharmaceutical. ZMapp was first used on humans during the 2014 West Africa Ebola virus outbreak, having only been previously tested on animals and not yet subjected to a randomized controlled trial. The 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.

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.

rVSV-ZEBOV vaccine Experimental vaccine against Ebola virus disease

Recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV), also known as Ebola Zaire vaccine live and sold under the brand name Ervebo, is a vaccine for adults that prevents Ebola caused by the Zaire ebolavirus. When used in ring vaccination, rVSV-EBOV has shown a high level of protection. Around half the people given the vaccine have mild to moderate adverse effects that include headache, fatigue, and muscle pain.

Ebola vaccine Any of several vaccines to prevent Ebola

Ebola vaccines are vaccines either approved or in development to prevent Ebola. 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.

Galidesivir

Galidesivir is an antiviral drug, an adenosine analog. It is 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, Marburg virus disease and Zika virus. Currently, Galidesivir is under phase 1 human trial in Brazil for Coronavirus.

Ebola virus disease treatment research

There is no cure or specific treatment for the Ebola virus disease that is currently approved for market, although various experimental treatments are being developed. For past and current Ebola epidemics, treatment has been primarily supportive in nature.

2018 Équateur province Ebola outbreak

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.

Kivu Ebola epidemic Ebola virus outbreak in the eastern DRC from 2018 to 2020

The Kivu Ebola epidemic began on 1 August 2018, when four cases of Ebola virus disease (EVD) were confirmed in the eastern region of Kivu in the Democratic Republic of the Congo (DRC). The Kivu outbreak also affected Ituri Province, whose first case was confirmed on 13 August, and in June 2019, the virus reached Uganda, having infected a 5-year-old Congolese boy who entered Uganda with his family, but was contained. In November 2018, the outbreak became the biggest Ebola outbreak in the DRC's history, and by November, it had become the second-largest Ebola outbreak in recorded history, behind only the 2013–2016 Western Africa epidemic. On 3 May 2019, nine months into the outbreak, the DRC outbreak death toll surpassed 1,000.

Jean-Jacques Muyembe-Tamfum Virologist known for working with Ebola

Jean-Jacques Muyembe is a Congolese microbiologist. He is the General Director of the Democratic Republic of the Congo Institut National pour la Recherche Biomedicale (INRB). He was part of team at the Yambuku Catholic Mission Hospital that investigated the first Ebola outbreak, and was part of the effort that discovered Ebola as a new disease, although his exact role is still subject to controversy. In 2016, he led the research that designed, along with other researchers at the INRB and the National Institute of Health Vaccine Research Center in the US, one of the most promising treatment for Ebola, mAb114. The treatment was successfully experimented during recent outbreaks in the DRC, on the express decision of the then DRC Minister of Health, Dr Oly Ilunga, despite a prior negative advice from the World Health Organization.

REGN-EB3 is an experimental biopharmaceutical treatment comprising three monoclonal antibodies under development by Regeneron Pharmaceuticals to treat Ebola virus disease. In August 2019, Congolese health officials announced that REGN-EB3 and a similar monoclonal antibody treatment, mAb114, were more effective than two other treatments being used at the time.

Nancy Sullivan (biologist) American cell biologist

Nancy Jean Sullivan is an American cell biologist researching filovirus immunology and vaccine development. She is a senior investigator and chief of the biodefense research section at the Vaccine Research Center. Her team discovered the monoclonal antibody, mAb114.

Atoltivimab/maftivimab/odesivimab, sold under the brand name Inmazeb, is a fixed-dose combination of three monoclonal antibodies for the treatment of Zaire ebolavirus. It contains atoltivimab, maftivimab, and odesivimab-ebgn.

References

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  9. ↑ Molteni M (12 August 2019). "Ebola is Now Curable. Here's How The New Treatments Work". Wired. Retrieved 13 August 2019.
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  12. ↑ Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. (August 2011). "Ebola virus entry requires the cholesterol transporter Niemann-Pick C1". Nature. 477 (7364): 340–3. Bibcode:2011Natur.477..340C. doi:10.1038/nature10348. PMC   3175325 . PMID   21866103.
  13. ↑ "Ridgeback Biotherapeutics LP announces licensing of mAb114, an experimental Ebola treatment, from the National Institute of Allergy and Infectious Diseases". www.prnewswire.com. Ridgeback Biotherapeutics LP. Retrieved 2019-08-17.
  14. ↑ "About Us". Ridgebackbio. Retrieved 2019-08-17.
  15. ↑ "Ridgeback Biotherapeutics LP Announces Orphan Drug Designation for mAb114". www.prnewswire.com. Ridgeback Biotherapeutics LP. Retrieved 2019-08-17.
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  20. ↑ "FDA Approves First Treatment for Ebola Virus". U.S. Food and Drug Administration (FDA) (Press release). 14 October 2020. Retrieved 14 October 2020.PD-icon.svgThis article incorporates text from this source, which is in the public domain.
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