Natalizumab

Identification

Name
Natalizumab
Accession Number
DB00108  (BTD00083, BIOD00083)
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

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 Natalizumab was voluntarily withdrawn from U.S. market because of risk of Progressive multifocal leukoencephalopathy (PML).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.

Protein structure
Db00108
Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
  • Anti-alpha4 integrin
  • Anti-VLA4
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TysabriSolution300 mgIntravenousBiogen2006-11-21Not applicableCanada
TysabriInjection300 mg/15mLIntravenousBiogen2004-11-23Not applicableUs
TysabriInjection300 mg/15mLIntravenousElan Pharmaceuticals2004-11-232016-06-30Us
Categories
UNII
3JB47N2Q2P
CAS number
189261-10-7

Pharmacology

Indication

For treatment of multiple sclerosis.

Associated Conditions
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
Human
ULow affinity immunoglobulin gamma Fc region receptor III-BNot AvailableHuman
UComplement C1r subcomponentNot AvailableHuman
UComplement C1q subcomponent subunit ANot AvailableHuman
UComplement C1q subcomponent subunit BNot AvailableHuman
UComplement C1q subcomponent subunit CNot AvailableHuman
ULow affinity immunoglobulin gamma Fc region receptor III-ANot AvailableHuman
UHigh affinity immunoglobulin gamma Fc receptor INot AvailableHuman
ULow affinity immunoglobulin gamma Fc region receptor II-aNot AvailableHuman
ULow affinity immunoglobulin gamma Fc region receptor II-bNot AvailableHuman
ULow affinity immunoglobulin gamma Fc region receptor II-cNot AvailableHuman
UIntercellular adhesion molecule 1Not AvailableHuman
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]
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Natalizumab is combined with 2-Methoxyethanol.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Natalizumab is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbataceptThe risk or severity of adverse effects can be increased when Natalizumab is combined with Abatacept.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Natalizumab.
AbetimusThe risk or severity of adverse effects can be increased when Natalizumab is combined with Abetimus.
AbituzumabThe risk or severity of adverse effects can be increased when Natalizumab is combined with Abituzumab.
ActeosideThe risk or severity of adverse effects can be increased when Natalizumab is combined with Acteoside.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Natalizumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Natalizumab is combined with Adecatumumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Natalizumab.
Food Interactions
Not Available

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. [PubMed:12510039]
External Links
PubChem Substance
46505849
ChEMBL
CHEMBL1201607
Therapeutic Targets Database
DAP001094
PharmGKB
PA164747191
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Natalizumab
ATC Codes
L04AA23 — Natalizumab
AHFS Codes
  • 92:20.00 — Immunomodulatory Agents
FDA label
Download (96 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedTreatmentRelapsing Forms of Multiple Sclerosis1
1Active Not RecruitingBasic ScienceSchizophrenic Disorders1
1Active Not RecruitingTreatmentInclusion Body Myositis (IBM)1
1CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
1CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS) / Secondary Progressive Multiple Sclerosis (SPMS)1
1, 2TerminatedTreatmentMultiple Myeloma (MM)1
2CompletedNot AvailableDisseminated Sclerosis1
2CompletedTreatmentAcute Ischemic Stroke (AIS)2
2CompletedTreatmentCrohn's Disease (CD)2
2CompletedTreatmentDisseminated Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
2CompletedTreatmentMultiple Sclerosis, Primary Progressive / Secondary Progressive Multiple Sclerosis (SPMS)1
2CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)3
2RecruitingTreatmentEpilepsy, Focal Seizures, Partial Seizures1
2RecruitingTreatmentGraft Versus Host Disease (GVHD)1
2RecruitingTreatmentGraft Versus Host Disease, Acute1
2TerminatedTreatmentRelapsing Multiple Sclerosis (RMS)1
2TerminatedTreatmentRheumatoid Arthritis2
2, 3CompletedTreatmentDisseminated Sclerosis1
2, 3RecruitingTreatmentDisseminated Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
3CompletedTreatmentCrohn's Disease (CD)3
3CompletedTreatmentDisseminated Sclerosis1
3CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)3
3Not Yet RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
3TerminatedNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)1
3TerminatedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
3TerminatedTreatmentSecondary Progressive Multiple Sclerosis (SPMS)1
4Active Not RecruitingTreatmentDisseminated Sclerosis1
4CompletedNot AvailableCrohn's Disease (CD)1
4CompletedNot AvailableDisseminated Sclerosis1
4CompletedBasic ScienceDisseminated Sclerosis1
4CompletedDiagnosticDisseminated Sclerosis1
4CompletedSupportive CareRelapsing Remitting Multiple Sclerosis (RRMS)1
4CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)3
4Not Yet RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4RecruitingOtherDisseminated Sclerosis1
4RecruitingTreatmentDisseminated Sclerosis1
4TerminatedTreatmentRelapsing Multiple Sclerosis (RMS)1
4TerminatedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4Unknown StatusTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4WithdrawnTreatmentCrohn's Disease (CD)1
4WithdrawnTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
Not AvailableActive Not RecruitingNot AvailableProgressive Multifocal Leukoencephalopathy1
Not AvailableActive Not RecruitingNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)2
Not AvailableCompletedNot AvailableDisseminated Sclerosis4
Not AvailableCompletedNot AvailableRelapsing Multiple Sclerosis (RMS)1
Not AvailableCompletedNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)3
Not AvailableCompletedSupportive CareDisseminated Sclerosis1
Not AvailableCompletedTreatmentDisseminated Sclerosis1
Not AvailableRecruitingNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)2
Not AvailableTerminatedNot AvailableCrohn's Disease (CD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Biogen Idec Inc.
  • Elan Pharmaceuticals Inc.
  • Hospira Inc.
Dosage forms
FormRouteStrength
InjectionIntravenous300 mg/15mL
SolutionIntravenous300 mg
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)

Taxonomy

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

Targets

Kind
Protein
Organism
Human
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. [PubMed:16268663]
  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. [PubMed:16634035]
  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. [PubMed:17461891]
  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. [PubMed:9389694]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serine-type peptidase activity
Specific Function
C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system.
Gene Name
C1R
Uniprot ID
P00736
Uniprot Name
Complement C1r subcomponent
Molecular Weight
80118.04 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Not Available
Specific Function
C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proe...
Gene Name
C1QA
Uniprot ID
P02745
Uniprot Name
Complement C1q subcomponent subunit A
Molecular Weight
26016.47 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Not Available
Specific Function
C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proe...
Gene Name
C1QB
Uniprot ID
P02746
Uniprot Name
Complement C1q subcomponent subunit B
Molecular Weight
26721.62 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Not Available
Specific Function
C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proe...
Gene Name
C1QC
Uniprot ID
P02747
Uniprot Name
Complement C1q subcomponent subunit C
Molecular Weight
25773.56 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Receptor for the Fc region of IgG. Binds complexed or aggregated IgG and also monomeric IgG. Mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as...
Gene Name
FCGR3A
Uniprot ID
P08637
Uniprot Name
Low affinity immunoglobulin gamma Fc region receptor III-A
Molecular Weight
29088.895 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Binds to the Fc region of immunoglobulins gamma. Low affinity receptor. By binding to IgG it initiates cellular responses against pathogens and soluble antigens. Promotes phagocytosis of opsonized ...
Gene Name
FCGR2A
Uniprot ID
P12318
Uniprot Name
Low affinity immunoglobulin gamma Fc region receptor II-a
Molecular Weight
35000.42 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Receptor for the Fc region of complexed or aggregated immunoglobulins gamma. Low affinity receptor. Involved in a variety of effector and regulatory functions such as phagocytosis of immune complex...
Gene Name
FCGR2B
Uniprot ID
P31994
Uniprot Name
Low affinity immunoglobulin gamma Fc region receptor II-b
Molecular Weight
34043.355 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Transmembrane signaling receptor activity
Specific Function
Receptor for the Fc region of complexed immunoglobulins gamma. Low affinity receptor. Involved in a variety of effector and regulatory functions such as phagocytosis of immune complexes and modulat...
Gene Name
FCGR2C
Uniprot ID
P31995
Uniprot Name
Low affinity immunoglobulin gamma Fc region receptor II-c
Molecular Weight
35577.96 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Kind
Protein
Organism
Human
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. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on November 14, 2018 12:38