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Identification
Name Denileukin diftitox
Accession Number DB00004 (BIOD00084, BTD00084)
Type biotech
Groups approved
Description

A recombinant DNA-derived cytotoxic protein composed of the amino acid sequences for diphtheria toxin fragments A and B (Met 1-Thr 387)-His followed by the sequences for interleukin-2 (IL-2; Ala 1-Thr 133). It is produced in an E. coli expression system.
Protein structure Db00004
Display: 3D Structure
Protein chemical formula C2560H4042N678O799S17
Protein average weight 57647.3000
Sequences 
>DB00004 sequence
MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK
YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG
TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY
EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS
EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK
TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN
FVESIINLFQVVHNSYNRPAYSPGHKTHAPTSSSTKKTQLQLEHLLLDLQMILNGINNYK
NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVI
VLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT

FASTA
Synonyms
Diphtheria toxin precursor
DT
NAD(+--diphthamide ADP- ribosyltransferase)
Salts Not Available
Brand names
Name Company
Ontak Seragen Inc
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
CAS number 173146-27-5
Taxonomy
Kingdom Organic
Classes
  • Polypeptides
Substructures
  • Polypeptides
Pharmacology
Indication For treatment of cutaneous T-cell lymphoma
Pharmacodynamics Denileukin diftitox (Ontak) directs the cytocidal action of diphtheria toxin to cells which express the IL-2 receptor. The human IL-2 receptor exists in three forms, low (CD25), intermediate (CD122/CD132) and high (CD25/CD122/CD132) affinity. Malignant cells expressing one or more of the subunits of the IL-2 receptor are found in certain leukemias and lymphomas including cutaneous T-cell lymphoma (CTCL). Ontak interacts with the high affinity IL-2 receptor on the cell surface and inhibits cellular protein synthesis, resulting in cell death within hours.
Mechanism of action Denileukin diftitox binds to the high-affinity IL-2 receptor complex. The IL-2 receptor (Tac) subunit is expressed on activated but not resting lymphocytes. The diphtheria toxin associated with Ontak then selectively kills the IL-2 bearing cells.
Absorption Not Available
Volume of distribution
  • 0.06 to 0.09 L/kg
Protein binding Not Available
Metabolism Not Available
Route of elimination Not Available
Half life 70-80 min
Clearance
  • 0.6 – 2.0 mL/min/kg [Lymphoma]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers
Dosage forms
Form Route Strength
Solution Intravenous
Prices
Unit description Cost Unit
Ontak 150 mcg/ml vial 878.4 USD 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
hydrophobicity -0.301 Not Available
isoelectric point 5.45 Not Available
References
Synthesis Reference Not Available
General Reference
  1. Turturro F: Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders. Expert Rev Anticancer Ther. 2007 Jan;7(1):11-7. Pubmed
  2. Park M, Liu GT, Piltz-Seymour J, Wisda CL, Rook AH, Junkins-Hopkins JM, Nasta SD, Kim EJ: Vision loss following denileukin diftitox treatment: a case report of possible posterior ischemic optic neuropathy. Leuk Lymphoma. 2007 Apr;48(4):808-11. Pubmed
External Links
Resource Link
UniProt P00587 Link_out
Genbank V01536 Link_out
PharmGKB PA164750594 Link_out
RxList http://www.rxlist.com/cgi/generic2/denileukin.htm Link_out
Drugs.com http://www.drugs.com/cdi/denileukin-diftitox.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Denileukin_diftitox Link_out
ATC Codes
  • L01XX29
AHFS Codes Not Available
PDB Entries
FDA label show (434 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Rilonacept decreases effects of toxoids by pharmacodynamic antagonism.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions Not Available
Targets

1. Interleukin-2 receptor alpha chain

Pharmacological action: yes
Actions: binder

Receptor for interleukin-2

Organism class: human
UniProt ID: P01589 Link_out
Gene: IL2RA Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  3. Kiyokawa T, Shirono K, Hattori T, Nishimura H, Yamaguchi K, Nichols JC, Strom TB, Murphy JR, Takatsuki K: Cytotoxicity of interleukin 2-toxin toward lymphocytes from patients with adult T-cell leukemia. Cancer Res. 1989 Jul 15;49(14):4042-6. Pubmed
  4. Murphy JR, Kelley VE, Strom TB: Interleukin 2 toxin: a step toward selective immunomodulation. Am J Kidney Dis. 1988 Feb;11(2):159-62. Pubmed
  5. Duvic M, Talpur R: Optimizing denileukin diftitox (Ontak) therapy. Future Oncol. 2008 Aug;4(4):457-69. Pubmed
  6. Turturro F: Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders. Expert Rev Anticancer Ther. 2007 Jan;7(1):11-7. Pubmed
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Interleukin-2 receptor subunit beta

Pharmacological action: yes
Actions: agonist

Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2

Organism class: human
UniProt ID: P14784 Link_out
Gene: IL2RB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Foss F, Demierre MF, DiVenuti G: A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2005 Jul 15;106(2):454-7. Epub 2005 Apr 5. Pubmed
  2. Foss F: Clinical experience with denileukin diftitox (ONTAK). Semin Oncol. 2006 Feb;33(1 Suppl 3):S11-6. Pubmed
  3. Duvic M, Talpur R: Optimizing denileukin diftitox (Ontak) therapy. Future Oncol. 2008 Aug;4(4):457-69. Pubmed
  4. Turturro F: Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders. Expert Rev Anticancer Ther. 2007 Jan;7(1):11-7. Pubmed
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Cytokine receptor common gamma chain

Pharmacological action: unknown

Common subunit for the receptors for a variety of interleukins

Organism class: human
UniProt ID: P31785 Link_out
Gene: IL2RG Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Foss F, Demierre MF, DiVenuti G: A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2005 Jul 15;106(2):454-7. Epub 2005 Apr 5. Pubmed
  2. Foss F: Clinical experience with denileukin diftitox (ONTAK). Semin Oncol. 2006 Feb;33(1 Suppl 3):S11-6. Pubmed
  3. Foss FM: DABIL-2 (denileukin diftitox, ONTAK): a new fusion protein technology. Clin Lymphoma. 2000 Nov;1 Suppl 1:S27-31. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on September 29, 2010 14:34