NAV

Denileukin diftitox

Identification

Summary

Denileukin diftitox is a recombinant cytotoxic protein based on a combination of diphtheria toxin fragments and interleukin-2 used to treat cutaneous T-cell lymphoma by targeting the interleukin-2 receptor.

Generic Name
Denileukin diftitox
DrugBank Accession Number
DB00004
Background

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.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Interleukin-based products / Fusion proteins
Protein Structure
Protein Chemical Formula
C2560H4042N678O799S17
Protein Average Weight
57647.3 Da
Sequences
>DB00004 sequence
MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK
YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG
TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY
EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS
EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK
TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN
FVESIINLFQVVHNSYNRPAYSPGHKTHAPTSSSTKKTQLQLEHLLLDLQMILNGINNYK
NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVI
VLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
Download FASTA Format
Synonyms
  • Denileukin
  • Denileukin diftitox
  • Interleukin-2/diptheria toxin fusion protein
External IDs
  • DAB-389IL2
  • DAB389 IL2
  • DAB389IL2
  • LY-335348
  • LY335348

Pharmacology

Indication

For treatment of cutaneous T-cell lymphoma

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Associated Conditions
Contraindications & Blackbox Warnings
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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.

TargetActionsOrganism
AInterleukin-2 receptor subunit alpha
binder
Humans
AInterleukin-2 receptor subunit beta
agonist
Humans
UCytokine receptor common subunit gammaNot AvailableHumans
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]
Adverse Effects
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Toxicity

Not Available

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.
DrugInteraction
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ArticaineThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Articaine.
BenzocaineThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Benzocaine.
Benzyl alcoholThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Benzyl alcohol.
BupivacaineThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Bupivacaine.
ButacaineThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Butacaine.
ButambenThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Butamben.
CapsaicinThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Capsaicin.
ChloroprocaineThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Chloroprocaine.
CinchocaineThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Cinchocaine.
CocaineThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Cocaine.
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Food Interactions
Not Available

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OntakInjection, solution150 ug/1mLIntravenousEisai Limited2013-11-012013-11-01US flag

Categories

ATC Codes
L01XX29 — Denileukin diftitox
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
25E79B5CTM
CAS number
173146-27-5

References

General References
  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. [Article]
  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. [Article]
UniProt
P00587
Genbank
V01536
PubChem Substance
46506950
RxNav
214470
ChEMBL
CHEMBL1201550
Therapeutic Targets Database
DAP001098
PharmGKB
PA164750594
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Denileukin_diftitox
FDA label
Download (434 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentCutaneous T Cell Lymphomas (CTCL)1
4CompletedTreatmentCutaneous T Cell Lymphomas (CTCL) / Mycosis Fungoides (MF) / Sezary Syndrome2
2CompletedSupportive CareDrug/Agent Toxicity by Tissue/Organ / Malignant Lymphomas1
2CompletedTreatmentB Cell Lymphoma (BCL)1
2CompletedTreatmentB Cell Lymphoma (BCL) / Low Grade Lymphoma / Non-Hodgkin's Lymphoma (NHL)1
2CompletedTreatmentChronic Lymphocytic Leukemia (CLL)1
2CompletedTreatmentEpithelial Ovarian Cancer / Extraovarian Peritoneal Cancer / Fallopian Tube Carcinoma1
2CompletedTreatmentGraft Versus Host Disease (cGvHD) / Immune System Disorders1
2CompletedTreatmentLeukemias1
2CompletedTreatmentLeukemias / Systemic Mastocytosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Eisai Inc.
  • Hollister-Stier Laboratories LLC
  • Ligand Pharmaceuticals Inc.
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous150 ug/1mL
Prices
Unit descriptionCostUnit
Ontak 150 mcg/ml vial878.4USD 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
hydrophobicity-0.301Not Available
isoelectric point5.45Not Available

Targets

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Details1. Interleukin-2 receptor subunit alpha
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Interleukin-2 receptor activity
Specific Function
Receptor for interleukin-2. The receptor is involved in the regulation of immune tolerance by controlling regulatory T cells (TREGs) activity. TREGs suppress the activation and expansion of autorea...
Gene Name
IL2RA
Uniprot ID
P01589
Uniprot Name
Interleukin-2 receptor subunit alpha
Molecular Weight
30818.915 Da
References
  1. 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. [Article]
  2. Murphy JR, Kelley VE, Strom TB: Interleukin 2 toxin: a step toward selective immunomodulation. Am J Kidney Dis. 1988 Feb;11(2):159-62. [Article]
  3. Duvic M, Talpur R: Optimizing denileukin diftitox (Ontak) therapy. Future Oncol. 2008 Aug;4(4):457-69. doi: 10.2217/14796694.4.4.457. [Article]
  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. [Article]
Details2. Interleukin-2 receptor subunit beta
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Interleukin-2 receptor activity
Specific Function
Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2.
Gene Name
IL2RB
Uniprot ID
P14784
Uniprot Name
Interleukin-2 receptor subunit beta
Molecular Weight
61116.59 Da
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. [Article]
  2. Foss F: Clinical experience with denileukin diftitox (ONTAK). Semin Oncol. 2006 Feb;33(1 Suppl 3):S11-6. [Article]
  3. Duvic M, Talpur R: Optimizing denileukin diftitox (Ontak) therapy. Future Oncol. 2008 Aug;4(4):457-69. doi: 10.2217/14796694.4.4.457. [Article]
  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. [Article]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Details3. Cytokine receptor common subunit gamma
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Interleukin-2 binding
Specific Function
Common subunit for the receptors for a variety of interleukins.
Gene Name
IL2RG
Uniprot ID
P31785
Uniprot Name
Cytokine receptor common subunit gamma
Molecular Weight
42286.68 Da
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. [Article]
  2. Foss F: Clinical experience with denileukin diftitox (ONTAK). Semin Oncol. 2006 Feb;33(1 Suppl 3):S11-6. [Article]
  3. Foss FM: DAB(389)IL-2 (denileukin diftitox, ONTAK): a new fusion protein technology. Clin Lymphoma. 2000 Nov;1 Suppl 1:S27-31. [Article]

Drug created at June 13, 2005 13:24 / Updated at February 03, 2022 21:04