Chemistry:MAb114

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Short description: Monoclonal antibody that is being trialed as a treatment for Ebola virus disease


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]

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 Unites 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]

References

  1. ↑ 1.0 1.1 "NIH begins testing Ebola treatment in early-stage trial". National Institutes of Health (NIH). 2018-05-23. https://www.nih.gov/news-events/news-releases/nih-begins-testing-ebola-treatment-early-stage-trial. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 "Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody". Science 351 (6279): 1339–42. March 2016. doi:10.1126/science.aad5224. PMID 26917593. Bibcode: 2016Sci...351.1339C. 
  3. ↑ 3.0 3.1 3.2 Hayden, Erika Check (2016-02-26). "Ebola survivor's blood holds promise of new treatment". Nature. doi:10.1038/nature.2016.19440. ISSN 1476-4687. https://www.nature.com/news/ebola-survivor-s-blood-holds-promise-of-new-treatment-1.19440. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study". Lancet 393 (10174): 889–898. March 2019. doi:10.1016/S0140-6736(19)30036-4. PMID 30686586. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Clinical trial number NCT03478891 for "Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Healthy Adults" at ClinicalTrials.gov
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "NIH VideoCast - CC Grand Rounds: Response to an Outbreak: Ebola Virus Monoclonal Antibody (mAb114) Rapid Clinical Development". https://videocast.nih.gov/summary.asp?Live=31594&bhcp=1. 
  7. ↑ 7.0 7.1 Kingsley-Hall, Alison. "Congo's experimental mAb114 Ebola treatment appears successful: authorities | Central Africa". http://www.theafricareport.com/Central-Africa/congos-experimental-mab114-ebola-treatment-appears-successful-authorities.html. 
  8. ↑ 8.0 8.1 McNeil, Donald G. (12 August 2019). "A Cure for Ebola? Two New Treatments Prove Highly Effective in Congo". The New York Times. https://www.nytimes.com/2019/08/12/health/ebola-outbreak-cure.html. 
  9. ↑ Molteni, Megan (12 August 2019). "Ebola is Now Curable. Here's How The New Treatments Work". Wired. https://www.wired.com/story/ebola-is-now-curable-heres-how-the-new-treatments-work/. 
  10. ↑ 10.0 10.1 "Structural and molecular basis for Ebola virus neutralization by protective human antibodies". Science 351 (6279): 1343–6. March 2016. doi:10.1126/science.aad6117. PMID 26917592. Bibcode: 2016Sci...351.1343M. 
  11. ↑ "Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection". Nature 477 (7364): 344–8. August 2011. doi:10.1038/nature10380. PMID 21866101. Bibcode: 2011Natur.477..344C. 
  12. ↑ "Ebola virus entry requires the cholesterol transporter Niemann-Pick C1". Nature 477 (7364): 340–3. August 2011. doi:10.1038/nature10348. PMID 21866103. Bibcode: 2011Natur.477..340C. 
  13. ↑ "Ridgeback Biotherapeutics LP announces licensing of mAb114, an experimental Ebola treatment, from the National Institute of Allergy and Infectious Diseases". Ridgeback Biotherapeutics LP. https://www.prnewswire.com/news-releases/ridgeback-biotherapeutics-lp-announces-licensing-of-mab114-an-experimental-ebola-treatment-from-the-national-institute-of-allergy-and-infectious-diseases-300765146.html. 
  14. ↑ "About Us". https://www.ridgebackbio.com/about-us. 
  15. ↑ "Ridgeback Biotherapeutics LP Announces Orphan Drug Designation for mAb114". Ridgeback Biotherapeutics LP. https://www.prnewswire.com/news-releases/ridgeback-biotherapeutics-lp-announces-orphan-drug-designation-for-mab114-300859467.html. 
  16. ↑ Check Hayden, Erika (May 2018). "Experimental drugs poised for use in Ebola outbreak". Nature 557 (7706): 475–476. doi:10.1038/d41586-018-05205-x. ISSN 0028-0836. PMID 29789732. Bibcode: 2018Natur.557..475C. 
  17. ↑ WHO: Consultation on Monitored Emergency Use of Unregistered and Investigational Interventions for Ebola virus Disease. https://www.who.int/emergencies/ebola/MEURI-Ebola.pdf
  18. ↑ Mole, Beth (2019-08-13). "Two Ebola drugs boost survival rates, according to early trial data". https://arstechnica.com/science/2019/08/two-ebola-drugs-boost-survival-rates-according-to-early-trial-data/. 
  19. ↑ "Independent monitoring board recommends early termination of Ebola therapeutics trial in DRC because of favorable results with two of four candidates". 2019-08-12. https://www.nih.gov/news-events/news-releases/independent-monitoring-board-recommends-early-termination-ebola-therapeutics-trial-drc-because-favorable-results-two-four-candidates. 




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