Atoltivimab

Identification

Summary

Atoltivimab is part of a product containing three monoclonal IgG1κ antibodies directed against the GP<sub>1,2</sub> glycoprotein of Zaire ebolavirus. Together, these three antibodies act to neutralize viral particles and to recruit immune effectors for the destruction of both viral particles and infected cells.

Brand Names
Inmazeb
Generic Name
Atoltivimab
DrugBank Accession Number
DB15898
Background

Ebola virus (EBOV) remains an important human pathogen within the Ebolavirus genus, having been responsible for at least 17 known outbreaks with an average case fatality rate of 43.92%.1 Immune therapy using monoclonal antibodies (mAbs) is becoming an increasingly attractive therapeutic method to combat infectious diseases due to its rapid development, low toxicity, and high specificity.3 The chief surface target of EBOV particles is the GP1,2 glycoprotein, which also appears on the surface of EBOV-infected cells, offering opportunities for both neutralizing and cytotoxic (i.e. through Fc-mediated immune effector function) antibody effects to play a role in combatting EBOV infection.1,2 A recent large-scale study elucidated that both neutralizing and Fc-mediated functions of antibodies were important for therapeutic benefit in animal models of EBOV infection.3

INMAZEB™, formerly referred to as REGN-EB3, combines the three humanized IgG1κ mAbs Atoltivimab (REGN 3470), Odesivimab (REGN 3471), and Maftivimab (REGN 3479) in equimolar proportions. All three mAbs bind to a distinct portion of the GP1,2 glycoprotein and collectively provide neutralizing and Fc-mediated immune effector function against EBOV in vitro and protection against EBOV infection in vivo. INMAZEB™ is produced by Regeneron Pharmaceuticals and was granted FDA approval on October 14, 2020.4

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6448H9954N1726O2002S44
Protein Average Weight
145097.54 Da (Peptide only)
Sequences
Not Available
Synonyms
  • Atoltivimab
External IDs
  • REGN-3470
  • REGN3470
  • WHO 11032

Pharmacology

Indication

Atoltivimab is indicated in combination with Odesivimab and Maftivimab for the treatment of Zaire ebolavirus infection in adult and pediatric patients, including neonates born to a mother who has been confirmed positive by RT-PCR for Zaire ebolavirus infection. This combination has not been established as efficacious for any other species within either the Ebolavirus or Marburgvirus genera; special care should be taken to evaluate the susceptibility of circulating Zaire ebolavirus strains before beginning treatment, and the possible emergence of resistance should be monitored.4

Pharmacology
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Associated Conditions
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Contraindications
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Pharmacodynamics

Atoltivimab is a fully-humanized IgG1κ monoclonal antibody (mAb) directed against the GP1,2 glycoprotein that provides both neutralizing and Fc-dependent immune-mediated activity against Zaire ebolavirus. As a mAb, Atoltivimab exhibits low toxicity and is generally well tolerated but does include the risk of potentially life-threatening hypersensitivity reactions.4

Mechanism of action

Ebola virus (EBOV) is one of several viruses within the Ebolavirus genus known to infect humans with an average case fatality rate of 43.92%.1 EBOV particles expose the GP1,2 glycoprotein on their surface, which comprises a trimer of GP1 and GP2 subunit heterodimers, with the subunits connected by a disulfide bond. GP1,2 plays an important role in both cell surface attachment/entry and eventual lysosomal escape through binding to the NPC intracellular cholesterol transporter 1/Niemann-Pick C1 protein (NPC1). In this manner, GP1,2 is integral to the pathogenic cycle of EBOV.1,2

Atoltivimab is a fully-humanized IgG1κ monoclonal antibody (mAb) directed against the EBOV GP1,2 glycoprotein, which binds the GP1,2 glycan cap parallel to the viral surface with a binding affinity (KD) of between 7.74 and 7.84 nM.2,4 Atoltivimab exhibits strong (<90%) neutralization of chimeric lentiviral particles expressing EBOV GP1,2 with a half-maximal inhibitory concentration (IC50) value of 0.27 nM. In addition, Atoltivimab is capable of dose-dependent activation of FcγRIIIa signalling in effector cells in the presence of GP1,2-expressing cells with a half-maximal effective concentration (EC50) of 2.9 nM.2 Combined with Odesivimab and Maftivimab, Atoltivimab works to block EBOV cell infection and lysosomal escape, as well as the potential antibody-dependent cell-mediated killing of EBOV-infected cells.1,2,3,4

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

Atoltivimab administered to healthy subjects at 50 mg/kg produced a mean Cmax of 1220 ± 101 mg/L and a mean AUC0-∞ of 17,100 ± 4480 mg*day/L.4

Volume of distribution

Atoltivimab administered to healthy subjects at 50 mg/kg produced a mean steady-state volume of distribution of 58.2 ± 2.66 mL/kg.4

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Atoltivimab administered to healthy subjects at 50 mg/kg has a mean elimination half-life of 21.2 ± 3.36 days.4

Clearance

Atoltivimab administered to healthy subjects at 50 mg/kg has a mean clearance of 3.08 ± 0.719 mL/day/kg.4

Adverse Effects
Adverseeffects
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Toxicity

Not Available

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 Atoltivimab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Atoltivimab.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Atoltivimab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Atoltivimab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Atoltivimab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Atoltivimab.
AmivantamabThe risk or severity of adverse effects can be increased when Atoltivimab is combined with Amivantamab.
AnifrolumabThe risk or severity of adverse effects can be increased when Anifrolumab is combined with Atoltivimab.
AnsuvimabThe risk or severity of adverse effects can be increased when Atoltivimab is combined with Ansuvimab.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Atoltivimab.
Interactions
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Food Interactions
No interactions found.

Products

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
InmazebAtoltivimab (241.7 mg/14.5mL) + Maftivimab (241.7 mg/14.5mL) + Odesivimab (241.7 mg/14.5mL)Injection, solutionIntravenousRegeneron Pharmaceuticals, Inc.2020-10-14Not applicableUS flag
InmazebAtoltivimab (483.3 mg/14.5mL) + Maftivimab (483.3 mg/14.5mL) + Odesivimab (483.3 mg/14.5mL)Injection, solutionIntravenousRegeneron Pharmaceuticals, Inc.2021-07-29Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Zaire ebolavirus (strain Mayinga-76)

Chemical Identifiers

UNII
FJZ07Q63VY
CAS number
2135632-29-8

References

Synthesis Reference

Pascal KE, Dudgeon D, Trefry JC, Anantpadma M, Sakurai Y, Murin CD, Turner HL, Fairhurst J, Torres M, Rafique A, Yan Y, Badithe A, Yu K, Potocky T, Bixler SL, Chance TB, Pratt WD, Rossi FD, Shamblin JD, Wollen SE, Zelko JM, Carrion R Jr, Worwa G, Staples HM, Burakov D, Babb R, Chen G, Martin J, Huang TT, Erlandson K, Willis MS, Armstrong K, Dreier TM, Ward AB, Davey RA, Pitt MLM, Lipsich L, Mason P, Olson W, Stahl N, Kyratsous CA: Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates. J Infect Dis. 2018 Nov 22;218(suppl_5):S612-S626. doi: 10.1093/infdis/jiy285.

General References
  1. Jacob ST, Crozier I, Fischer WA 2nd, Hewlett A, Kraft CS, Vega MA, Soka MJ, Wahl V, Griffiths A, Bollinger L, Kuhn JH: Ebola virus disease. Nat Rev Dis Primers. 2020 Feb 20;6(1):13. doi: 10.1038/s41572-020-0147-3. [Article]
  2. Pascal KE, Dudgeon D, Trefry JC, Anantpadma M, Sakurai Y, Murin CD, Turner HL, Fairhurst J, Torres M, Rafique A, Yan Y, Badithe A, Yu K, Potocky T, Bixler SL, Chance TB, Pratt WD, Rossi FD, Shamblin JD, Wollen SE, Zelko JM, Carrion R Jr, Worwa G, Staples HM, Burakov D, Babb R, Chen G, Martin J, Huang TT, Erlandson K, Willis MS, Armstrong K, Dreier TM, Ward AB, Davey RA, Pitt MLM, Lipsich L, Mason P, Olson W, Stahl N, Kyratsous CA: Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates. J Infect Dis. 2018 Nov 22;218(suppl_5):S612-S626. doi: 10.1093/infdis/jiy285. [Article]
  3. Saphire EO, Schendel SL, Gunn BM, Milligan JC, Alter G: Antibody-mediated protection against Ebola virus. Nat Immunol. 2018 Nov;19(11):1169-1178. doi: 10.1038/s41590-018-0233-9. Epub 2018 Oct 17. [Article]
  4. FDA Approved Drug Products: INMAZEB (atoltivimab, maftivimab, and odesivimab-ebgn) injection [Link]
RxNav
2461338
Wikipedia
Atoltivimab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Subjects (HS)1
Not AvailableAvailableNot AvailableEbolavirus Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Zaire ebolavirus (strain Mayinga-76)
Pharmacological action
Yes
Actions
Antagonist
Curator comments
Atoltivimab is a fully-humanized IgG1κ monoclonal antibody (mAb) directed against the EBOV GP1,2 glycoprotein, which binds the GP1,2 glycan cap parallel to the viral surface with a binding affinity (KD) of between 7.74 and 7.84 nM.[A221830, L17320]
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. Pascal KE, Dudgeon D, Trefry JC, Anantpadma M, Sakurai Y, Murin CD, Turner HL, Fairhurst J, Torres M, Rafique A, Yan Y, Badithe A, Yu K, Potocky T, Bixler SL, Chance TB, Pratt WD, Rossi FD, Shamblin JD, Wollen SE, Zelko JM, Carrion R Jr, Worwa G, Staples HM, Burakov D, Babb R, Chen G, Martin J, Huang TT, Erlandson K, Willis MS, Armstrong K, Dreier TM, Ward AB, Davey RA, Pitt MLM, Lipsich L, Mason P, Olson W, Stahl N, Kyratsous CA: Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates. J Infect Dis. 2018 Nov 22;218(suppl_5):S612-S626. doi: 10.1093/infdis/jiy285. [Article]
  2. FDA Approved Drug Products: INMAZEB (atoltivimab, maftivimab, and odesivimab-ebgn) injection [Link]

Drug created on October 16, 2020 15:12 / Updated on March 04, 2021 09:26