Natalizumab

Identification

Summary

Natalizumab is a monoclonal anti-integrin antibody which binds to the alpha 4 subunit of integrins to prevent migration of immune cells, and is used to treat Crohn's disease or multiple sclerosis.

Brand Names
Tysabri
Generic Name
Natalizumab
DrugBank Accession Number
DB00108
Background

Humanized IgG4k monoclonal antibody produced in murine myeloma cells. Natalizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to a4-integrin. Natalizumab was voluntarily withdrawn from U.S. market because of risk of Progressive multifocal leukoencephalopathy (PML). It was returned to market July, 2006.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db00108
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
Not Available
Synonyms
  • Anti-alpha4 integrin
  • Anti-VLA4
  • Natalizumab
External IDs
  • AN100226M

Pharmacology

Indication

For treatment of multiple sclerosis.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells, and their counter-receptors present on endothelial cells of the vessel wall. The clinical effect of natalizumab in multiple sclerosis may be a secondary result of its blockade of the molecular interaction of a 4b 1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain. α4-integrin is required for white blood cells to move into organs, therefore, natalizumab prevents these immune cells from crossing blood vessel walls to reach affected organs thereby decreasing inflamation.

Mechanism of action

Binds to the α4-subunit of α4b 1 and α4b 7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their counter-receptor(s).

TargetActionsOrganism
AIntegrin alpha-4
antibody
Humans
ULow affinity immunoglobulin gamma Fc region receptor III-BNot AvailableHumans
UIntercellular adhesion molecule 1Not AvailableHumans
UHigh affinity immunoglobulin gamma Fc receptor INot AvailableHumans
Absorption

Not Available

Volume of distribution
  • 5.7 ± 1.9 L [Multiple Sclerosis (MS) Patients]
  • 5.2 ± 2.8 L [Crohn's Disease (CD) Patients]
Protein binding

Not Available

Metabolism

Most likely removed by opsonization via the reticuloendothelial system when bound to leukocytes.

Route of elimination

Not Available

Half-life

11 ± 4 days

Clearance
  • 16 +/- 5 mL/hour [patients with MS who did not have PML receiving the repeat IV administration of a 300 mg dose]
  • 22 +/- 22 mL/hour [Patients with Crohn's Disease receiving the repeat IV administration of a 300 mg dose]
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
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Natalizumab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Natalizumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Natalizumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Natalizumab.
AducanumabThe risk or severity of adverse effects can be increased when Natalizumab is combined with Aducanumab.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Natalizumab.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Natalizumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Natalizumab.
AlirocumabThe risk or severity of adverse effects can be increased when Natalizumab is combined with Alirocumab.
Allogeneic processed thymus tissueThe therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Natalizumab.
Interactions
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Food Interactions
No interactions found.

Products

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International/Other Brands
Antegren
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TysabriInjection, solution, concentrate300 mgIntravenousBiogen Netherlands B.V.2020-12-15Not applicableEU flag
TysabriInjection300 mg/15mLIntravenousBiogen Inc.2004-11-23Not applicableUS flag
TysabriSolution300 mg / 15 mLIntravenousBiogen2006-11-21Not applicableCanada flag
TysabriInjection300 mg/15mLIntravenousElan Pharmaceuticals2004-11-232016-06-30US flag

Categories

ATC Codes
L04AA23 — Natalizumab
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
  • Humans and other mammals

Chemical Identifiers

UNII
3JB47N2Q2P
CAS number
189261-10-7

References

General References
  1. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, Vyhnalek P, Zadorova Z, Palmer T, Donoghue S: Natalizumab for active Crohn's disease. N Engl J Med. 2003 Jan 2;348(1):24-32. [Article]
PubChem Substance
46505849
RxNav
354770
ChEMBL
CHEMBL1201607
Therapeutic Targets Database
DAP001094
PharmGKB
PA164747191
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Natalizumab
FDA label
Download (96 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableCrohn's Disease (CD)1
4CompletedNot AvailableMultiple Sclerosis1
4CompletedBasic ScienceMultiple Sclerosis1
4CompletedDiagnosticMultiple Sclerosis1
4CompletedSupportive CareRelapsing Remitting Multiple Sclerosis (RRMS)1
4CompletedTreatmentMultiple Sclerosis1
4CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)3
4RecruitingOtherMultiple Sclerosis1
4RecruitingTreatmentMultiple Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
4RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Biogen Idec Inc.
  • Elan Pharmaceuticals Inc.
  • Hospira Inc.
Dosage Forms
FormRouteStrength
InjectionIntravenous300 mg/15mL
Injection, solutionSubcutaneous150 MG
Injection, solution, concentrateIntravenous300 mg
Injection, solution, concentrateIntravenous; Parenteral300 MG
SolutionIntravenous300 mg / 15 mL
Injection, solution, concentrateIntravenous
SolutionIntravenous300 mg/15mL
Solution, concentrateIntravenous300 mg
Injection, solution, concentrateIntravenous20 mg/1ml
Prices
Unit descriptionCostUnit
Tysabri 300 mg/15 ml vial207.31USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)61 °C (FAB fragment), 71 °C (whole mAb)Vermeer, A.W.P. & Norde, W., Biophys. J. 78:394-404 (2000)

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Metal ion binding
Specific Function
Integrins alpha-4/beta-1 (VLA-4) and alpha-4/beta-7 are receptors for fibronectin. They recognize one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. They are...
Gene Name
ITGA4
Uniprot ID
P13612
Uniprot Name
Integrin alpha-4
Molecular Weight
114898.745 Da
References
  1. Sheremata WA, Minagar A, Alexander JS, Vollmer T: The role of alpha-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications. CNS Drugs. 2005;19(11):909-22. [Article]
  2. Niino M, Bodner C, Simard ML, Alatab S, Gano D, Kim HJ, Trigueiro M, Racicot D, Guerette C, Antel JP, Fournier A, Grand'Maison F, Bar-Or A: Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol. 2006 May;59(5):748-54. [Article]
  3. Stuve O, Bennett JL: Pharmacological properties, toxicology and scientific rationale for the use of natalizumab (Tysabri) in inflammatory diseases. CNS Drug Rev. 2007 Spring;13(1):79-95. [Article]
  4. Craddock CF, Nakamoto B, Andrews RG, Priestley GV, Papayannopoulou T: Antibodies to VLA4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice. Blood. 1997 Dec 15;90(12):4779-88. [Article]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Receptor for the Fc region of immunoglobulins gamma. Low affinity receptor. Binds complexed or aggregated IgG and also monomeric IgG. Contrary to III-A, is not capable to mediate antibody-dependent...
Gene Name
FCGR3B
Uniprot ID
O75015
Uniprot Name
Low affinity immunoglobulin gamma Fc region receptor III-B
Molecular Weight
26215.64 Da
References
  1. Weber F, Breustedt D, Schlicht S, Meyer CA, Niewoehner J, Ebeling M, Freskgard PO, Bruenker P, Singer T, Reth M, Iglesias A: First Infusion Reactions are Mediated by FcgammaRIIIb and Neutrophils. Pharm Res. 2018 Jun 27;35(9):169. doi: 10.1007/s11095-018-2448-8. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Virus receptor activity
Specific Function
ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2). During leukocyte trans-endothelial migration, ICAM1 engagement promotes the assembly of endothelial api...
Gene Name
ICAM1
Uniprot ID
P05362
Uniprot Name
Intercellular adhesion molecule 1
Molecular Weight
57824.785 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Receptor signaling protein activity
Specific Function
High affinity receptor for the Fc region of immunoglobulins gamma. Functions in both innate and adaptive immune responses.
Gene Name
FCGR1A
Uniprot ID
P12314
Uniprot Name
High affinity immunoglobulin gamma Fc receptor I
Molecular Weight
42631.525 Da
References
  1. Dudek S, Weissmuller S, Anzaghe M, Miller L, Sterr S, Hoffmann K, Hengel H, Waibler Z: Human Fcgamma receptors compete for TGN1412 binding that determines the antibody's effector function. Eur J Immunol. 2019 Jul;49(7):1117-1126. doi: 10.1002/eji.201847924. Epub 2019 Apr 29. [Article]

Drug created on June 13, 2005 13:24 / Updated on October 19, 2021 07:39