Atoltivimab

Identification

Summary

Atoltivimab is part of a product containing three monoclonal IgG1κ antibodies directed against the GP1,2 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 GP_1,2 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 GP_1,2 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

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Associated Conditions

Hemorrhagic Fever, Ebola

Contraindications & Blackbox Warnings

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Pharmacodynamics

Atoltivimab is a fully-humanized IgG1κ monoclonal antibody (mAb) directed against the GP_1,2 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 GP_1,2 glycoprotein on their surface, which comprises a trimer of GP₁ and GP₂ subunit heterodimers, with the subunits connected by a disulfide bond. GP_1,2 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, GP_1,2 is integral to the pathogenic cycle of EBOV.^1,2

Atoltivimab is a fully-humanized IgG1κ monoclonal antibody (mAb) directed against the EBOV GP_1,2 glycoprotein, which binds the GP_1,2 glycan cap parallel to the viral surface with a binding affinity (K_D) of between 7.74 and 7.84 nM.^2,4 Atoltivimab exhibits strong (<90%) neutralization of chimeric lentiviral particles expressing EBOV GP_1,2 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 GP_1,2-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

Target	Actions	Organism
AEnvelope glycoprotein	antagonist	Zaire ebolavirus (strain Mayinga-76)

Absorption

Atoltivimab administered to healthy subjects at 50 mg/kg produced a mean C_max of 1220 ± 101 mg/L and a mean AUC_0-∞ 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

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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.

Drug	Interaction
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Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Atoltivimab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Atoltivimab.
Adenovirus type 7 vaccine live	The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Atoltivimab.
Aducanumab	The risk or severity of adverse effects can be increased when Aducanumab is combined with Atoltivimab.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Atoltivimab.
Alirocumab	The risk or severity of adverse effects can be increased when Alirocumab is combined with Atoltivimab.
Amivantamab	The risk or severity of adverse effects can be increased when Atoltivimab is combined with Amivantamab.
Anifrolumab	The risk or severity of adverse effects can be increased when Anifrolumab is combined with Atoltivimab.
Ansuvimab	The risk or severity of adverse effects can be increased when Atoltivimab is combined with Ansuvimab.
Anthrax immune globulin human	The risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Atoltivimab.

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Food Interactions

No interactions found.

Products

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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Inmazeb	Atoltivimab (241.7 mg/14.5mL) + Maftivimab (241.7 mg/14.5mL) + Odesivimab (241.7 mg/14.5mL)	Injection, solution	Intravenous	Regeneron Pharmaceuticals, Inc.	2020-10-14	Not applicable
Inmazeb	Atoltivimab (483.3 mg/14.5mL) + Maftivimab (483.3 mg/14.5mL) + Odesivimab (483.3 mg/14.5mL)	Injection, solution	Intravenous	Regeneron Pharmaceuticals, Inc.	2021-07-29	Not applicable

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

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]
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]
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]
FDA Approved Drug Products: INMAZEB (atoltivimab, maftivimab, and odesivimab-ebgn) injection [Link]

External Links

RxNav: 2461338
Wikipedia: Atoltivimab

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2	Not Yet Recruiting	Prevention	Ebolavirus Disease	1
1	Completed	Basic Science	Healthy Subjects (HS)	1
Not Available	Available	Not Available	Ebolavirus Disease	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Intravenous

Prices

Not Available

Patents

Not Available

Properties

State: Liquid
Experimental Properties: Not Available

Targets

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Details1. Envelope glycoprotein

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 GP_1,2 glycoprotein, which binds the GP_1,2 glycan cap parallel to the viral surface with a binding affinity (K_D) 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

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]
FDA Approved Drug Products: INMAZEB (atoltivimab, maftivimab, and odesivimab-ebgn) injection [Link]

Drug created at October 16, 2020 15:12 / Updated at February 03, 2022 19:50

Atoltivimab

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References