Ansuvimab

Identification

Summary

Ansuvimab is a fully human monoclonal IgG1 antibody directed against the GP1,2 surface protein of Zaire ebolavirus that is an effective treatment for Ebola virus disease.

Brand Names
Ebanga
Generic Name
Ansuvimab
DrugBank Accession Number
DB16385
Background

Infection with pathogenic filoviruses, such as Zaire ebolavirus (Ebola virus, EBOV), can cause severe hemorrhagic fever in humans, resulting in frequent outbreaks with case fatality rates as high as 90%.1,2 Virtually all steps of the EBOV lifecycle have been targeted for therapeutic development. However, to date, the most successful method appears to be the development of monoclonal antibodies (mAbs) against the GP1,2 surface glycoprotein, as evidenced by the previously approved INMAZEB™ (REGN-EB3, a cocktail of atoltivimab, odesivimab, and maftivimab), the now approved ansuvimab, and ZMapp, which remains in clinical trials.1 Ansuvimab, formerly mAb114, is a fully human IgG1 mAb derived from a survivor of the 1995 Kikwit EBOV outbreak 11 years after infection, which displays strong glycan-independent binding to a conserved region of the GP1,2 protein that is responsible for interacting with the host NPC1 protein to mediate EBOV endolysosomal escape, a key step in the EBOV lifecycle.3,4,5 A randomized, controlled trial of four investigational therapies for Ebola virus disease (EVD) in the Democratic Republic of Congo during a previous outbreak that began in 2018 compared ansuvimab, REGN-EB3, ZMapp, and remdesivir, a nucleoside analogue designed to inhibit viral replication, showed ansuvimab and REGN-EB3 to be superior, with improved patient survival and faster viral clearance rates.6

Ansuvimab received FDA approval on December 21, 2020, and is currently marketed as Ebanga by Ridgeback Biotherapeutics, LP. Ansuvimab is just the second FDA-approved treatment for EVD.7

Type
Biotech
Groups
Approved, Investigational
Synonyms
  • Ansuvimab
  • ansuvimab-zykl
External IDs
  • Anti-ebola monoclonal antibody mAb114
  • EboV mAb114
  • EVB-114
  • EVB114
  • MAB-114
  • MAb114
  • VRC-EBOMAB092-00-AB
  • WHO 11568

Pharmacology

Indication

Ansuvimab is indicated for the treatment of Zaire ebolavirus infection in adult and pediatric patients, including neonates born to a mother who tests positive for Zaire ebolavirus by RT-PCR.7

Ansuvimab has not been shown to be effective against other species within the Ebolavirus and Marburgvirus genera; factors such as the possible emergence of resistant strains suggest local information on circulating Zaire ebolavirus strains should be consulted before initiating treatment.7

Pharmacology
Accelerate your drug discovery research with the industry’s only fully connected ADMET dataset, ideal for:
Machine Learning
Data Science
Drug Discovery
Accelerate your drug discovery research with our fully connected ADMET dataset
Learn more
Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
Contraindications & Blackbox Warnings
With our commercial data, access important information on dangerous risks, contraindications, and adverse effects.
Learn more
Our Blackbox Warnings cover Risks, Contraindications, and Adverse Effects
Learn more
Pharmacodynamics

Ansuvimab is a human IgG1 monoclonal antibody directed against the Zaire ebolavirus GP1,2 surface glycoprotein that is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells. The exposure-response relationship of ansuvimab is not currently understood, although the recommended treatment comprises only a single dose. Despite a good overall safety profile, ansuvimab treatment carries a risk of potentially life-threatening hypersensitivity reactions, including infusion-related reactions; in the case of hypersensitivity reactions, ansuvimab should be discontinued, and supportive care initiated immediately.7

Mechanism of action

Zaire ebolavirus (Ebola virus, EBOV) is one of six species within the Ebolavirus genus, which itself is one of six genera within the Filoviridae family.1 Infection with pathogenic filoviruses such as EBOV in humans can result in hemorrhagic fever with very high fatality rates (25-90%).1,2 Following infection, a variable latency period of ~2-21 days occurs before the onset of symptoms, which are vague at first, including fatigue, fever, aches, myalgia, and gastrointestinal complaints, but that progress in severe disease to both internal and external bleeding, multiorgan failure, secondary infections, meningoencephalitis, hypotension, and shock.1,2 The pathogenesis of EBOV is poorly understood but is thought to be multifactorial: immune suppression, cytokine dysregulation, vascular dysfunction, and abnormal coagulation.1

EBOV is a non-segmented negative-sense RNA virus whose genome comprises seven genes, including the GP1,2 glycoprotein involved in host cell entry and subsequent viral escape into the cytoplasm. GP1,2 binds to one of several possible host receptors such as various lectins and TYRO3 receptor tyrosine kinases, β1 integrins, the asialoglycoprotein receptor, human folate receptor-α, and TIM1. Following internalization into endolysosomes by macropinocytosis, GP1,2 is cleaved by host cathepsins into a fusion-competent form termed GPCL, which subsequently binds the Niemann-Pick C1 protein (NPC1) to induce fusion of the host endolysosomal and viral membranes that releases the viral nucleocapsids into the host cytoplasm.1

The EBOV GP is a class I fusion protein comprising GP1 and GP2 subunits, transcribed as a single gene and proteolytically processed into individual subunits linked by disulphide bonds; three subunit heterodimers subsequently associate to form the mature chalice-shaped GP1,2.1,3 Ansuvimab (formerly mAb114) is a fully human IgG1 monoclonal antibody (mAb) derived from an Ebola virus disease (EVD) survivor from the 1995 Kikwit EBOV outbreak 11 years after infection that binds to GP1,2 over a region encompassing both the glycan cap and GP1 core, although the glycan cap is dispensable for binding.3,4,5 Furthermore, structural studies reveal that ansuvimab binds to regions of the GP1 core thought to be important for GPCL interaction with NPC1 and blocks NPC1-GP interactions in vitro.3 Further in vitro studies revealed that ansuvimab exhibits strong GP binding (EC50 of 0.02 μg/mL), the ability to neutralize GP-expressing lentiviral particles (IC50 of 0.09 μg/mL), and strong antibody-dependent cell-mediated cytotoxicity (ADCC) at concentrations of 0.03 μg/mL.4 Hence, the proposed ansuvimab mechanism of action is through direct blockage of EBOV endolysosome escape and ADCC-mediated killing of EBOV-infected cells.

TargetActionsOrganism
AEnvelope glycoprotein
antagonist
Zaire ebolavirus (strain Mayinga-76)
Absorption

The absorption of ansuvimab was evaluated in 18 healthy volunteers aged 18-60 years in an open-label phase 1 study. Ansuvimab administered at 5 mg/kg produced a Cmax of 198.45 ± 45.15 μg/mL, a Tmax of 3.21 ± 1.56 h, and an AUC0-28d of 1480 ± 304 μg*day/mL. The corresponding values for 25 mg/kg were: Cmax of 829.38 ± 237.40 μg/mL, Tmax of 2.99 ± 2.16 h, and AUC0-28d of 8586 ± 900 μg*day/mL, while the corresponding values for 50 mg/kg were: Cmax of 1961.21 ± 339.83 μg/mL, Tmax of 2.75 ± 1.63 h, and AUC0-28d of 18588 ± 3627 μg*day/mL.5 Overall, the pharmacokinetic profile of ansuvimab is consistent with other IgG1 monoclonal antibodies.7

Volume of distribution

The steady-state volume of distribution in healthy volunteers administered a single dose of 5 mg/kg, 25 mg/kg, or 50 mg/kg ansuvimab was 5.08 ± 0.88, 3.93 ± 0.50, and 4.16 ± 0.74 L, respectively.5

Protein binding

Not Available

Metabolism

Ansuvimab is expected to be degraded by various proteolytic and catabolic processes within the body, like other monoclonal antibodies.

Route of elimination

Not Available

Half-life

The half-life of ansuvimab following a single administration of 5 mg/kg, 25 mg/kg, or 50 mg/kg was 20.1 ± 6.9, 26.7 ± 3.8, and 23.6 (no calculated standard deviation available) days, respectively.5

Clearance

The clearance of ansuvimab following a single administration of 5 mg/kg, 25 mg/kg, or 50 mg/kg was 199 ± 45, 108 ± 21, and 115 ± 15 mL/day, respectively.5

Adverse Effects
Medicalerrors
Reduce medical errors
and improve treatment outcomes with our comprehensive & structured data on drug adverse effects.
Learn more
Reduce medical errors & improve treatment outcomes with our adverse effects data
Learn more
Toxicity

Toxicity information regarding ansuvimab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hypotension, tachycardia, tachypnea, pyrexia, chills, diarrhea, vomiting, and hypersensitivity reactions including infusion-related reactions. Symptomatic and supportive measures are recommended.7

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Ansuvimab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Ansuvimab.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Ansuvimab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Ansuvimab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Ansuvimab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Ansuvimab.
AmivantamabThe risk or severity of adverse effects can be increased when Ansuvimab is combined with Amivantamab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Ansuvimab.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Ansuvimab.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Ansuvimab.
Interactions
Improve patient outcomes
Build effective decision support tools with the industry’s most comprehensive drug-drug interaction checker.
Learn more
Food Interactions
No interactions found.

Products

Products
Comprehensive & structured drug product info
From application numbers to product codes, connect different identifiers through our commercial datasets.
Learn more
Easily connect various identifiers back to our datasets
Learn more
International/Other Brands
Ebanga
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Ebanga400 mg/8mLIntravenousRidgeback Biotherapeutics, Lp2020-12-21Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Zaire ebolavirus (strain Mayinga-76)

Chemical Identifiers

UNII
TG8IQ19NG2
CAS number
2375952-29-5

References

Synthesis Reference

Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, Ploquin A, Doria-Rose NA, Staupe RP, Bailey M, Shi W, Choe M, Marcus H, Thompson EA, Cagigi A, Silacci C, Fernandez-Rodriguez B, Perez L, Sallusto F, Vanzetta F, Agatic G, Cameroni E, Kisalu N, Gordon I, Ledgerwood JE, Mascola JR, Graham BS, Muyembe-Tamfun JJ, Trefry JC, Lanzavecchia A, Sullivan NJ: Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science. 2016 Mar 18;351(6279):1339-42. doi: 10.1126/science.aad5224.

General References
  1. Hoenen T, Groseth A, Feldmann H: Therapeutic strategies to target the Ebola virus life cycle. Nat Rev Microbiol. 2019 Oct;17(10):593-606. doi: 10.1038/s41579-019-0233-2. Epub 2019 Jul 24. [Article]
  2. Inungu J, Iheduru-Anderson K, Odio OJ: Recurrent Ebolavirus disease in the Democratic Republic of Congo: update and challenges. AIMS Public Health. 2019 Nov 20;6(4):502-513. doi: 10.3934/publichealth.2019.4.502. eCollection 2019. [Article]
  3. Misasi J, Gilman MS, Kanekiyo M, Gui M, Cagigi A, Mulangu S, Corti D, Ledgerwood JE, Lanzavecchia A, Cunningham J, Muyembe-Tamfun JJ, Baxa U, Graham BS, Xiang Y, Sullivan NJ, McLellan JS: Structural and molecular basis for Ebola virus neutralization by protective human antibodies. Science. 2016 Mar 18;351(6279):1343-6. doi: 10.1126/science.aad6117. Epub 2016 Feb 25. [Article]
  4. Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, Ploquin A, Doria-Rose NA, Staupe RP, Bailey M, Shi W, Choe M, Marcus H, Thompson EA, Cagigi A, Silacci C, Fernandez-Rodriguez B, Perez L, Sallusto F, Vanzetta F, Agatic G, Cameroni E, Kisalu N, Gordon I, Ledgerwood JE, Mascola JR, Graham BS, Muyembe-Tamfun JJ, Trefry JC, Lanzavecchia A, Sullivan NJ: Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science. 2016 Mar 18;351(6279):1339-42. doi: 10.1126/science.aad5224. Epub 2016 Feb 25. [Article]
  5. Gaudinski MR, Coates EE, Novik L, Widge A, Houser KV, Burch E, Holman LA, Gordon IJ, Chen GL, Carter C, Nason M, Sitar S, Yamshchikov G, Berkowitz N, Andrews C, Vazquez S, Laurencot C, Misasi J, Arnold F, Carlton K, Lawlor H, Gall J, Bailer RT, McDermott A, Capparelli E, Koup RA, Mascola JR, Graham BS, Sullivan NJ, Ledgerwood JE: Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study. Lancet. 2019 Mar 2;393(10174):889-898. doi: 10.1016/S0140-6736(19)30036-4. Epub 2019 Jan 24. [Article]
  6. Mulangu S, Dodd LE, Davey RT Jr, Tshiani Mbaya O, Proschan M, Mukadi D, Lusakibanza Manzo M, Nzolo D, Tshomba Oloma A, Ibanda A, Ali R, Coulibaly S, Levine AC, Grais R, Diaz J, Lane HC, Muyembe-Tamfum JJ, Sivahera B, Camara M, Kojan R, Walker R, Dighero-Kemp B, Cao H, Mukumbayi P, Mbala-Kingebeni P, Ahuka S, Albert S, Bonnett T, Crozier I, Duvenhage M, Proffitt C, Teitelbaum M, Moench T, Aboulhab J, Barrett K, Cahill K, Cone K, Eckes R, Hensley L, Herpin B, Higgs E, Ledgerwood J, Pierson J, Smolskis M, Sow Y, Tierney J, Sivapalasingam S, Holman W, Gettinger N, Vallee D, Nordwall J: A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019 Dec 12;381(24):2293-2303. doi: 10.1056/NEJMoa1910993. Epub 2019 Nov 27. [Article]
  7. DailyMed: EBANGA (ansuvimab) injection [Link]
RxNav
2472152
Wikipedia
Ansuvimab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Not Yet RecruitingPreventionEbolavirus Disease1
2, 3CompletedTreatmentEbola Viruses1
1CompletedTreatmentHealthy Adult Immune Responses to Vaccine1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets
Accelerate your drug discovery research
with our fully connected ADMET & drug target dataset.
Learn more
Accelerate your drug discovery research with our ADMET & drug target dataset
Learn more
Kind
Protein
Organism
Zaire ebolavirus (strain Mayinga-76)
Pharmacological action
Yes
Actions
Antagonist
General Function
Envelope glycoprotein Trimeric GP1,2 complexes form the virion surface spikes and mediate the viral entry processes, with GP1 acting as the receptor-binding subunit and GP2 as the membrane fusion subunit. At later times of infection, downregulates the expression of various host cell surface molecules that are essential for immune surveillance and cell adhesion. Down-modulates several integrins including ITGA1, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGAV and ITGB1. This decrease in cell adhesion molecules may lead to cell detachment, contributing to the disruption of blood vessel integrity and hemorrhages developed during infection (cytotoxicity). Interacts with host TLR4 and thereby stimulates the differentiation and activation of monocytes leading to bystander death of T-lymphocytes (PubMed:28542576). Downregulates as well the function of host natural killer cells (PubMed:30013549). Counteracts the antiviral effect of host BST2/tetherin that restricts release of progeny virions from infected cells. However, cooperates with VP40 and host BST2 to activate canonical NF-kappa-B pathway in a manner dependent on neddylation.
Specific Function
Identical protein binding
Gene Name
GP
Uniprot ID
Q05320
Uniprot Name
Envelope glycoprotein
Molecular Weight
74463.855 Da
References
  1. Misasi J, Gilman MS, Kanekiyo M, Gui M, Cagigi A, Mulangu S, Corti D, Ledgerwood JE, Lanzavecchia A, Cunningham J, Muyembe-Tamfun JJ, Baxa U, Graham BS, Xiang Y, Sullivan NJ, McLellan JS: Structural and molecular basis for Ebola virus neutralization by protective human antibodies. Science. 2016 Mar 18;351(6279):1343-6. doi: 10.1126/science.aad6117. Epub 2016 Feb 25. [Article]
  2. Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, Ploquin A, Doria-Rose NA, Staupe RP, Bailey M, Shi W, Choe M, Marcus H, Thompson EA, Cagigi A, Silacci C, Fernandez-Rodriguez B, Perez L, Sallusto F, Vanzetta F, Agatic G, Cameroni E, Kisalu N, Gordon I, Ledgerwood JE, Mascola JR, Graham BS, Muyembe-Tamfun JJ, Trefry JC, Lanzavecchia A, Sullivan NJ: Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science. 2016 Mar 18;351(6279):1339-42. doi: 10.1126/science.aad5224. Epub 2016 Feb 25. [Article]
  3. DailyMed: EBANGA (ansuvimab) injection [Link]

Drug created on December 22, 2020 16:06 / Updated on July 28, 2021 15:00