Idursulfase

Identification

Name
Idursulfase
Accession Number
DB01271
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Description

Idursulfase is a purified form of human iduronate-2-sulfatase, a lysosomal enzyme. Idursulfase is produced by recombinant DNA technology in a human cell line. Idursulfase is an enzyme that hydrolyzes the 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and heparan sulfate in the lysosomes of various cell types. Idursulfase is a 525-amino acid glycoprotein with a molecular weight of approximately 76 kilodaltons. The enzyme contains eight asparagine-linked glycosylation sites occupied by complex oligosaccharide structures. The enzyme activity of idursulfase is dependent on the post-translational modification of a specific cysteine to formylglycine.

Protein chemical formula
C2654H4000N688O774S14
Protein average weight
76000.0 Da
Sequences
>Idursulfase heavy chain
SETQANSTTDALNVLLIIVDDLRPSLGCYGDKLVRSPNIDQLASHSLLFQNAFAQQAVCA
PSRVSFLTGRRPDTTRLYDFNSYWRVHAGNFSTIPQYFKENGYVTMSVGKVFHPGISSNH
TDDSPYSWSFPPYHPSSEKYENTKTCRGPDGELHANLLCPVDVLDVPEGTLPDKQSTEQA
IQLLEKMKTSASPFFLAVGYHKPHIPFRYPKEFQKLYPLENITLAPDPEVPDGLPPVAYN
PWMDIRQREDVQALNISVPYGPIPVDFQRKIRQSYFASVSYLDTQVGRLLSALDDLQLAN
STIIAFTSDHGWALGEHGEWAKYSNFDVATHVPLIFYVPGRTASLPEAGEKLFPYLDPFD
SASQLMEPGRQSMDLVELVSLFPTLAGLAGLQVPPRCPVPSFHVELCREGKNLLKHFRFR
DLEEDPYLPG
>Idursulfase light chain
NPRELIAYSQYPRPSDIPQWNSDKPSLKDIKIMGYSIRTIDYRYTVWVGFNPDEFLANFS
DIHAGELYFVDSDPLQDHNMYNDSQGGDLFQLLMP
Download FASTA Format
Synonyms
  • Alpha-L-iduronate sulfate sulfatase
  • Iduronate 2-sulfatase
  • Idursulfasa
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ElapraseSolution2 mgIntravenousShire Human Genetic Therapies, Inc.2007-08-01Not applicableCanada
ElapraseSolution, concentrate6 mg/3mLIntravenousShire US Manufacturing Inc.2006-07-24Not applicableUs
Categories
UNII
5W8JGG2651
CAS number
50936-59-9

Pharmacology

Indication

For the treatment of Hunter syndrome in adults and children ages 5 and older.

Associated Conditions
Pharmacodynamics

Idursulfase is a purified form of the lysosomal enzyme human iduronate-2-sulfatase of recombinant DNA origin. It is designed to replace the natural enzyme, increasing catabolism of certain accumulated glycosaminoglycans (GAG), which abnormally accumulate in multiple tissue types in patients with mucopolysaccharidosis II (MPS-II, or Hunter syndrome).

Mechanism of action

Hunter's Syndrome is an X-linked recessive disease caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. This enzyme cleaves the terminal 2-O-sulfate moieties from the glycosaminoglycans (GAG) dermatan sulfate and heparan sulfate. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter's Syndrome, GAG progressively accumulate in the lysosomes of a variety of cells, leading to cellular engorgement, organomegaly, tissue destruction and organ system dysfunction. Treatment of Hunter's Syndrome patients with idursulfase provides exogenous enzyme for uptake into cellular lysosomes. Targeting of idursulfase to the lysosome occurs by endocytosis from the cell surface. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow specific binding of the enzymes to the M6P receptors on the cell surface, leading to cellular internalization of the enzyme, targeting to intracellular lysosomes and subsequent catabolism of accumulated GAG.

TargetActionsOrganism
ADermatan sulfateNot AvailableHuman
AHeparan sulfateNot AvailableHuman
NPerilipin-3Not AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

44 ± 19 minutes

Clearance
  • 3 mL/min/kg [Patients (7.7 – 27 years) with Hunter syndrome with treatment week 1(0.5 mg/kg ELAPRASE administered weekly as a 3-hour infusion)]
  • 3.4 mL/min/kg [patients (7.7 – 27 years) with Hunter syndrome with treatment week 27 (0.5 mg/kg ELAPRASE administered weekly as a 3-hour infusion)]
Toxicity

There is no experience with overdosage of Idursulfase in humans. Single intravenous doses of idursulfase up to 20 mg/kg were not lethal in male rats and cynomolgus monkeys (approximately 6.5 and 13 times, respectively, of the recommended human dose based on body surface area) and there were no clinical signs of toxicity.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
No interactions found.
Food Interactions
Not Available

References

General References
  1. Garcia AR, DaCosta JM, Pan J, Muenzer J, Lamsa JC: Preclinical dose ranging studies for enzyme replacement therapy with idursulfase in a knock-out mouse model of MPS II. Mol Genet Metab. 2007 Jun;91(2):183-90. Epub 2007 Apr 24. [PubMed:17459751]
  2. Zareba G: Idursulfase in Hunter syndrome treatment. Drugs Today (Barc). 2007 Nov;43(11):759-67. doi: 10.1358/dot.2007.43.11.1157619. [PubMed:18174963]
  3. Clarke LA: Idursulfase for the treatment of mucopolysaccharidosis II. Expert Opin Pharmacother. 2008 Feb;9(2):311-7. doi: 10.1517/14656566.9.2.311 . [PubMed:18201153]
  4. Burrow TA, Leslie ND: Review of the use of idursulfase in the treatment of mucopolysaccharidosis II. Biologics. 2008 Jun;2(2):311-20. [PubMed:19707363]
  5. Scarpa M: Mucopolysaccharidosis Type II . [PubMed:20301451]
  6. Wraith JE, Scarpa M, Beck M, Bodamer OA, De Meirleir L, Guffon N, Meldgaard Lund A, Malm G, Van der Ploeg AT, Zeman J: Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008 Mar;167(3):267-77. Epub 2007 Nov 23. [PubMed:18038146]
External Links
PubChem Substance
46507347
ChEMBL
CHEMBL1201826
PharmGKB
PA164749134
Drugs.com
Drugs.com Drug Page
Wikipedia
Idursulfase
ATC Codes
A16AB09 — Idursulfase
AHFS Codes
  • 44:00.00 — Enzymes

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Not Yet RecruitingTreatmentMucopolysaccharidosis II1
2, 3CompletedTreatmentHunter Syndrome / Mucopolysaccharidosis II (MPS II)1
2, 3CompletedTreatmentMucopolysaccharidosis II1
2, 3Enrolling by InvitationTreatmentHunter Syndrome1
4Active Not RecruitingTreatmentHunter Syndrome1
4CompletedTreatmentHunter Syndrome / MPS II / Mucopolysaccharidosis II1
Not AvailableCompletedNot AvailableHunter Syndrome1
Not AvailableCompletedNot AvailableMucopolysaccharidosis II1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Baxter International Inc.
  • Shire Inc.
Dosage forms
FormRouteStrength
SolutionIntravenous2 mg
Solution, concentrateIntravenous6 mg/3mL
Prices
Unit descriptionCostUnit
Elaprase 6 mg/3 ml vial1051.28USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

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
Small molecule
Organism
Human
Pharmacological action
Yes
References
  1. Burrow TA, Leslie ND: Review of the use of idursulfase in the treatment of mucopolysaccharidosis II. Biologics. 2008 Jun;2(2):311-20. [PubMed:19707363]
  2. Wraith JE, Scarpa M, Beck M, Bodamer OA, De Meirleir L, Guffon N, Meldgaard Lund A, Malm G, Van der Ploeg AT, Zeman J: Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008 Mar;167(3):267-77. Epub 2007 Nov 23. [PubMed:18038146]
  3. Garcia AR, Pan J, Lamsa JC, Muenzer J: The characterization of a murine model of mucopolysaccharidosis II (Hunter syndrome). J Inherit Metab Dis. 2007 Nov;30(6):924-34. Epub 2007 Sep 16. [PubMed:17876721]
2. Heparan sulfate
Kind
Small molecule
Organism
Human
Pharmacological action
Yes
References
  1. Burrow TA, Leslie ND: Review of the use of idursulfase in the treatment of mucopolysaccharidosis II. Biologics. 2008 Jun;2(2):311-20. [PubMed:19707363]
  2. Wraith JE, Scarpa M, Beck M, Bodamer OA, De Meirleir L, Guffon N, Meldgaard Lund A, Malm G, Van der Ploeg AT, Zeman J: Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008 Mar;167(3):267-77. Epub 2007 Nov 23. [PubMed:18038146]
  3. Garcia AR, Pan J, Lamsa JC, Muenzer J: The characterization of a murine model of mucopolysaccharidosis II (Hunter syndrome). J Inherit Metab Dis. 2007 Nov;30(6):924-34. Epub 2007 Sep 16. [PubMed:17876721]
Kind
Protein
Organism
Human
Pharmacological action
No
General Function
Not Available
Specific Function
Required for the transport of mannose 6-phosphate receptors (MPR) from endosomes to the trans-Golgi network.
Gene Name
PLIN3
Uniprot ID
O60664
Uniprot Name
Perilipin-3
Molecular Weight
47074.665 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]
  3. Clarke LA: Idursulfase for the treatment of mucopolysaccharidosis II. Expert Opin Pharmacother. 2008 Feb;9(2):311-7. doi: 10.1517/14656566.9.2.311 . [PubMed:18201153]
  4. Burrow TA, Leslie ND: Review of the use of idursulfase in the treatment of mucopolysaccharidosis II. Biologics. 2008 Jun;2(2):311-20. [PubMed:19707363]
  5. Wraith JE, Scarpa M, Beck M, Bodamer OA, De Meirleir L, Guffon N, Meldgaard Lund A, Malm G, Van der Ploeg AT, Zeman J: Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008 Mar;167(3):267-77. Epub 2007 Nov 23. [PubMed:18038146]

Drug created on May 16, 2007 14:17 / Updated on December 12, 2018 03:40