NAV

Natalizumab

Identification

Summary

Natalizumab is a monoclonal anti-integrin antibody used to treat Crohn's disease or multiple sclerosis.

Brand Names
Tysabri
Generic Name
Natalizumab
DrugBank Accession Number
DB00108
Background

Natalizumab is a recombinant humanized IgG4κ monoclonal antibody that binds to α4-integrin.8 While natalizumab was originally approved by the FDA to treat multiple sclerosis in 2004, it was withdrawn from the market following multiple reports of fatal progressive multifocal leukoencephalopathy (PML). In 2006, the FDA reintroduced the drug to the market for multiple sclerosis.2 Natalizumab was further approved by the FDA for the treatment of Crohn's Disease in January 2008.5

On August 24, 2023, the first biosimilar to natalizumab, natalizumab-sztn, was approved by the FDA.8 Natalizumab was approved by the European Commission on September 22, 2023.9

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Protein Chemical Formula
Not Available
Protein Average Weight
149000.0 Da (approximate)
Sequences
>Heavy chain
QVQLVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQRLEWMGRIDPANGYTKY
DPKFQGRVTITADTSASTAYMELSSLRSEDTAVYYCAREGYYGNYGVYAMDYWGQGTLVT
VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGG
PSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE
MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW
QEGNVFSCSVMHEALHNHYTQKSLSLSLGK
>Light chain
DIQMTQSPSSLSASVGDRVTITCKTSQDINKYMAWYQQTPGKAPRLLIHYTSALQPGIPS
RFSGSGSGRDYTFTISSLQPEDIATYYCLQYDNLWTFGQGTKVEIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. KEGG DRUG: Natalizumab [Link]
Download FASTA Format
Synonyms
  • Anti-alpha4 integrin
  • Anti-VLA4
  • IMMUNOGLOBULIN G4 (HUMAN-MOUSE MONOCLONAL AN100226 4-CHAIN ANTI-HUMAN INTEGRIN 4), DISULFIDE WITH HUMAN-MOUSE MONOCLONAL AN100226 LIGHT CHAIN, DIMER
  • IMMUNOGLOBULIN G4 (HUMAN-MOUSE MONOCLONAL AN100226 4-CHAIN ANTI-HUMAN INTEGRIN 4), DISULPHIDE WITH HUMAN-MOUSE MONOCLONAL AN100226 LIGHT CHAIN, DIMER
  • Natalizumab
External IDs
  • AN 100226
  • AN-100226
  • AN100226
  • AN100226M
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Pharmacology

Indication

Natalizumab is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults.6,7,9

It is also indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease with evidence of inflammation who have had an inadequate response to or are unable to tolerate, conventional therapies and inhibitors of TNF-α. It is not to be used in combination with immunosuppressants or inhibitors of TNF-α.6,7

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofRelapsing remitting multiple sclerosis (rrms)•••••••••••••••••••••••• •• •• ••••• ••• ••••• •••••••• ••••••••••••••••
Management ofRelapsing remitting multiple sclerosis (rrms)••••••••••••••••••••••••••
Management ofSecondary progressive multiple sclerosis (spms)••••••••••••••••••••••••••
Management ofSevere crohn's disease•••••••••••••••••••••••••••• •••• •••••••••••• ••••••••••••••••
Management ofModerate crohn’s disease•••••••••••••••••••••••••••• •••• •••••••••••• ••••••••••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Natalizumab is a disease-modifying drug that works to alleviate the symptoms of multiple sclerosis and Crohn’s disease by attenuating inflammation.2,4 A reduction in lesions was observed in patients with multiple sclerosis who received natalizumab.2 Natalizumab increases the number of circulating leukocytes, including lymphocytes, monocytes, basophils, and eosinophils;3,6 this effect is attributed to natalizumab inhibiting their transmigration out of the vascular space. Natalizumab does not affect the absolute count of circulating neutrophils.6

Mechanism of action

Integrins are transmembrane receptors and adhesion molecules that facilitate the chemotaxis of leukocytes to inflammation sites.2 Made up of multiple subunits, α4 integrins form heterodimers with β-subunits to form functional molecules.1 During inflammation, endothelial cells lining blood vessels are activated by cytokines. There is increased expression of cell adhesion molecules on the vascular endothelium, such as vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), expressed on vascular endothelial cells of the gastrointestinal tract. These cell adhesion molecules act as ligands or counter-receptors for α4 integrin receptors expressed primarily on lymphocytes, monocytes, and eosinophils. The interaction between cell adhesion molecules and α4 integrin facilitates the transmigration of leukocytes across the endothelium into inflamed parenchymal tissue, activation and proliferation of lymphocytes, and enhanced activity of local cytokines and chemokines. α4 integrin can also interact with extracellular matrix molecules such as fibronectin and osteopontin to further propagate inflammation.1,6 Natalizumab binds to the α4 subunit of α4β1 and α4β7 integrin receptors to block the α4-mediated adhesion of leukocytes to their counter-receptors. In vitro, natalizumab also blocks α4-mediated cell binding to osteopontin and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). In vivo, natalizumab may further inhibit the interaction of α4-expressing leukocytes with their ligand(s) in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells.6

The specific mechanism(s) by which natalizumab exerts its effects in multiple sclerosis and Crohn’s disease have not been fully defined. Lesions in multiple sclerosis (MS) are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves the interaction between adhesion molecules on inflammatory cells and their counter-receptors expressed on endothelial cells lining blood vessels. Natalizumab blocks the molecular interaction of α4β1-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; thereby, natalizumab reduces leukocyte migration into brain parenchyma and reduces plaque formation associated with MS.2,6

The interaction of the α4β7 integrin with the endothelial receptor MAdCAM1 has been implicated as an important contributor to chronic inflammation in Crohn’s disease (CD). MAdCAM-1 is mainly expressed on gut endothelial cells and is critical in homing T lymphocytes to gut lymph tissue found in Peyer’s patches. Increased MAdCAM-1 expression is often observed at active inflammation sites in patients with CD, suggesting that MAdCAM-1 may be involved in the recruitment of leukocytes to the mucosa. The clinical effect of natalizumab in CD may, therefore, be secondary to the blockade of the molecular interaction of the α4ß7 integrin receptor with MAdCAM-1 expressed on the venular endothelium at inflammatory foci. VCAM-1 expression has been found to be upregulated on colonic endothelial cells in a mouse model of inflammatory bowel disease and appears to play a role in leukocyte recruitment to sites of inflammation; however, the role of VCAM-1 in CD is unclear.6

TargetActionsOrganism
AIntegrin alpha-4
antibody
Humans
ULow affinity immunoglobulin gamma Fc region receptor III-B
ligand
Humans
UHigh affinity immunoglobulin gamma Fc receptor I
ligand
Humans
UIntercellular adhesion molecule 1
ligand
Humans
Absorption

Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD maximum observed serum concentration was 110 ± 52 mcg/mL. Mean average steady-state trough concentrations ranged from 23 mcg/mL to 29 mcg/mL. The observed time to steady-state was approximately 24 weeks after every four weeks of dosing.6

In patients with Crohn's Disease, the mean ± SD maximum observed serum concentration was 101 ± 34 mcg/mL. The mean ± SD average steady-state trough concentration was 10 ± 9 mcg/mL. The estimated time to steady-state was approximately 16 to 24 weeks after every four weeks of dosing. 6

Volume of distribution

Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD volume of distribution was 5.7 ± 1.9 L. In patients with Crohn's Disease, it was 5.2 ± 2.8 L.6

Protein binding

No information is available.

Metabolism

No information is available.

Route of elimination

No information is available.

Half-life

Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD half-life was 11 ± 4 days. In patients with Crohn's Disease, it was 10 ± 7 days.6

Clearance

Following the repeat intravenous administration of a 300 mg dose of natalizumab in patients with multiple sclerosis, the mean ± SD clearance was 16 ± 5 mL/hour. In patients with Crohn's Disease, it was 22 ± 22 mL/hour.6

Natalizumab clearance increased with body weight in a less-than-proportional manner. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold.

Adverse Effects
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Toxicity

There is limited information regarding the acute toxicity (LD50) and overdosage of natalizumab. The safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of natalizumab that can be safely administered has not been determined.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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
Integrate drug-drug
interactions in your software
AbataceptThe risk or severity of immunosuppression 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 immunosuppression 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.
Food Interactions
No interactions found.

Products

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International/Other Brands
Antegren
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TysabriInjection300 mg/15mLIntravenousElan Pharmaceuticals2004-11-232016-06-30US flag
TysabriSolution300 mg / 15 mLIntravenousBiogen2006-11-21Not applicableCanada flag
TysabriInjection, solution, concentrate150 mgIntravenousBiogen Netherlands B.V.2021-10-28Not applicableEU flag
TysabriInjection300 mg/15mLIntravenousBiogen Inc.2004-11-23Not applicableUS flag
TysabriInjection, solution, concentrate300 mgIntravenousBiogen Netherlands B.V.2020-12-15Not applicableEU 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. Brandstadter R, Katz Sand I: The use of natalizumab for multiple sclerosis. Neuropsychiatr Dis Treat. 2017 Jun 28;13:1691-1702. doi: 10.2147/NDT.S114636. eCollection 2017. [Article]
  2. Babaesfahani A, Khanna NR, Kuns B: Natalizumab. . [Article]
  3. 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]
  4. Pucci E, Giuliani G, Solari A, Simi S, Minozzi S, Di Pietrantonj C, Galea I: Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD007621. doi: 10.1002/14651858.CD007621.pub2. [Article]
  5. Dryden GW: Natalizumab for Moderate-to-Severe Crohn's Disease. Gastroenterol Hepatol (N Y). 2008 Apr;4(4):296. [Article]
  6. FDA Approved Drug Products: TYSABRI (natalizumab) injection, for intravenous use (April 2023) [Link]
  7. FDA Approved Drug Products: TYRUKO (natalizumab-sztn) injection, for intravenous use (August 2023) [Link]
  8. FDA News Release: FDA Approves First Biosimilar to Treat Multiple Sclerosis [Link]
  9. EMA Approved Drug Products: Tyruko (natalizumab) Intravenous Infusion [Link]
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

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
4Active Not RecruitingOtherMultiple Sclerosis1
4CompletedNot AvailableCrohn's Disease (CD)1
4CompletedNot AvailableMultiple Sclerosis1
4CompletedBasic ScienceMultiple Sclerosis1
4CompletedDiagnosticMultiple Sclerosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Biogen Idec Inc.
  • Elan Pharmaceuticals Inc.
  • Hospira Inc.
Dosage Forms
FormRouteStrength
Injection, solution, concentrateIntravenous300 mg
InjectionIntravenous300 mg/15mL
Injection, solutionSubcutaneous150 MG
Injection, solution, concentrateIntravenous150 mg
Injection, solution, concentrateIntravenous; Parenteral300 MG
SolutionIntravenous300 mg / 15 mL
SolutionIntravenous300 mg
SolutionIntravenous300 mg/15mL
SolutionSubcutaneous150.00 mg
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

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insights and accelerate drug research.
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Details1. Integrin alpha-4
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]
  6. FDA Approved Drug Products: TYSABRI (natalizumab) injection, for intravenous use (April 2023) [Link]
Details2. Low affinity immunoglobulin gamma Fc region receptor III-B
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Ligand
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]
Details3. High affinity immunoglobulin gamma Fc receptor I
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Ligand
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]
Details4. Intercellular adhesion molecule 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Ligand
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]

Drug created at June 13, 2005 13:24 / Updated at December 08, 2023 12:54