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binds to α4-integrin.⁸ While natalizumab was originally approved by the FDA to treat multiple sclerosis in 2004, it was withdrawn from the market following multiple reports of fatal progressive multifocal leukoencephalopathy (PML).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

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:

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

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

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

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

Target	Actions	Organism
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

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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Abatacept	The risk or severity of immunosuppression can be increased when Abatacept is combined with Natalizumab.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Natalizumab.
Adalimumab	The risk or severity of immunosuppression can be increased when Adalimumab is combined with Natalizumab.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Natalizumab.
Aducanumab	The risk or severity of adverse effects can be increased when Natalizumab is combined with Aducanumab.
Aldesleukin	The risk or severity of immunosuppression can be increased when Aldesleukin is combined with Natalizumab.
Alefacept	The risk or severity of immunosuppression can be increased when Alefacept is combined with Natalizumab.
Alemtuzumab	The risk or severity of immunosuppression can be increased when Alemtuzumab is combined with Natalizumab.
Alirocumab	The risk or severity of adverse effects can be increased when Natalizumab is combined with Alirocumab.
Allogeneic processed thymus tissue	The therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Natalizumab.

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Food Interactions

No interactions found.

Products

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International/Other Brands

Antegren

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Tysabri	Injection, solution, concentrate	150 mg	Intravenous	Biogen Netherlands B.V.	2021-10-28	Not applicable
Tysabri	Injection	300 mg/15mL	Intravenous	Biogen Inc.	2004-11-23	Not applicable
Tysabri	Injection, solution, concentrate	300 mg	Intravenous	Biogen Netherlands B.V.	2020-12-15	Not applicable
Tysabri	Injection	300 mg/15mL	Intravenous	Elan Pharmaceuticals	2004-11-23	2016-06-30
Tysabri	Solution	300 mg / 15 mL	Intravenous	Biogen	2006-11-21	Not applicable

Chemical Identifiers

UNII: 3JB47N2Q2P
CAS number: 189261-10-7

References

General References

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]
Babaesfahani A, Khanna NR, Kuns B: Natalizumab. . [Article]
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]
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]
Dryden GW: Natalizumab for Moderate-to-Severe Crohn's Disease. Gastroenterol Hepatol (N Y). 2008 Apr;4(4):296. [Article]
FDA Approved Drug Products: TYSABRI (natalizumab) injection, for intravenous use (April 2023) [Link]
FDA Approved Drug Products: TYRUKO (natalizumab-sztn) injection, for intravenous use (August 2023) [Link]
FDA News Release: FDA Approves First Biosimilar to Treat Multiple Sclerosis [Link]

External Links

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

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Other	Multiple Sclerosis	1
4	Completed	Not Available	Crohn's Disease (CD)	1
4	Completed	Not Available	Multiple Sclerosis	1
4	Completed	Basic Science	Multiple Sclerosis	1
4	Completed	Diagnostic	Multiple Sclerosis	1
4	Completed	Supportive Care	Relapsing Remitting Multiple Sclerosis (RRMS)	1
4	Completed	Treatment	Multiple Sclerosis	1
4	Completed	Treatment	Relapsing Remitting Multiple Sclerosis (RRMS)	3
4	Enrolling by Invitation	Treatment	Relapsing Remitting Multiple Sclerosis (RRMS)	1
4	Recruiting	Treatment	Multiple Sclerosis	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Biogen Idec Inc.
Elan Pharmaceuticals Inc.
Hospira Inc.

Dosage Forms

Form	Route	Strength
Injection	Intravenous	300 mg/15mL
Injection, solution	Subcutaneous	150 MG
Injection, solution, concentrate	Intravenous	150 mg
Injection, solution, concentrate	Intravenous; Parenteral	300 MG
Solution	Intravenous	300 mg
Solution	Intravenous	300 mg / 15 mL
Injection, solution, concentrate	Intravenous	300 mg
Solution	Intravenous	300 mg/15mL
Solution	Subcutaneous	150.00 mg
Solution, concentrate	Intravenous	300 mg
Injection, solution, concentrate	Intravenous	20 mg/1ml

Prices

Unit description	Cost	Unit
Tysabri 300 mg/15 ml vial	207.31USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Not Available

Properties

State

Liquid

Experimental Properties

Property	Value	Source
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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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

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]
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]
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]
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]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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

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

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

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 September 12, 2023 18:32

Natalizumab

Identification

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References

References

References

References