Identification
NameDenileukin diftitox
Accession NumberDB00004  (BTD00084, BIOD00084)
TypeBiotech
GroupsApproved, Investigational
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 structureDb00004
Related Articles
Protein chemical formulaC2560H4042N678O799S17
Protein average weight57647.3 Da
Sequences
>DB00004 sequence
MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK
YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG
TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY
EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS
EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK
TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN
FVESIINLFQVVHNSYNRPAYSPGHKTHAPTSSSTKKTQLQLEHLLLDLQMILNGINNYK
NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVI
VLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
Download FASTA Format
Synonyms
Diphtheria toxin precursor
DT
NAD(+--diphthamide ADP- ribosyltransferase)
External IDs Not Available
Product Ingredients Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OntakInjection, solution150 ug/mLIntravenousEisai Limited2008-10-152017-01-31Us
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNII25E79B5CTM
CAS number173146-27-5
Pharmacology
Indication

For treatment of cutaneous T-cell lymphoma

Structured Indications
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.

TargetKindPharmacological actionActionsOrganismUniProt ID
Interleukin-2 receptor subunit alphaProteinyes
binder
HumanP01589 details
Interleukin-2 receptor subunit betaProteinyes
agonist
HumanP14784 details
Cytokine receptor common subunit gammaProteinunknownNot AvailableHumanP31785 details
Related Articles
AbsorptionNot Available
Volume of distribution
  • 0.06 to 0.09 L/kg
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half life

70-80 min

Clearance
  • 0.6 - 2.0 mL/min/kg [Lymphoma]
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Denileukin diftitox.Approved
BevacizumabBevacizumab may increase the cardiotoxic activities of Denileukin diftitox.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Denileukin diftitox.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Denileukin diftitox.Approved, Investigational
DeslanosideDeslanoside may decrease the cardiotoxic activities of Denileukin diftitox.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Denileukin diftitox.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Denileukin diftitox.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Denileukin diftitox.Approved, Investigational
OleandrinAnvirzel may decrease the cardiotoxic activities of Denileukin diftitox.Experimental
OuabainOuabain may decrease the cardiotoxic activities of Denileukin diftitox.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Denileukin diftitox.Approved, Vet Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Denileukin diftitox.Approved, Investigational
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
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. [PubMed:17187516 ]
  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:17454642 ]
External Links
ATC CodesL01XX29
AHFS CodesNot Available
PDB Entries
FDA labelDownload (434 KB)
MSDSNot Available
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedTreatmentRenal Cancers1
1Active Not RecruitingTreatmentFallopian Tube Cancer / Ovarian Clear Cell Cystadenocarcinoma / Ovarian Endometrioid Adenocarcinoma / Ovarian Mixed Epithelial Carcinoma / Ovarian Mucinous Cystadenocarcinoma / Ovarian Serous Cystadenocarcinoma / Ovarian Undifferentiated Adenocarcinoma / Peritoneal Cavity Cancer / Recurrent Ovarian Epithelial Cancer / Stage III Ovarian Epithelial Cancer / Stage IV Ovarian Epithelial Cancer1
1CompletedTreatmentCancer, Breast / Colorectal Cancers / Lung Cancers / Malignant Neoplasm of Pancreas / Unspecified Adult Solid Tumor, Protocol Specific1
1CompletedTreatmentHER2-positive Breast Cancer / Recurrent Breast Cancer / Recurrent Non-small Cell Lung Cancer / Recurrent Ovarian Epithelial Cancer / Recurrent Ovarian Germ Cell Tumor / Stage IV Breast Cancer / Stage IV Non-Small Cell Lung Cancer / Stage IV Ovarian Epithelial Cancer / Stage IV Ovarian Germ Cell Tumor1
1CompletedTreatmentPeripheral T-Cell Lymphoma (PTCL)1
1TerminatedTreatmentMultiple Myeloma (MM)1
1WithdrawnTreatmentChronic Lymphocytic B-Leukemia1
1, 2Active Not RecruitingTreatmentMale Breast Cancer / Recurrent Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer1
1, 2CompletedTreatmentMelanoma (Skin)1
1, 2TerminatedTreatmentMetastatic Head and Neck Squamous Cell Carcinoma / Recurrent Head and Neck Squamous Cell Carcinoma / Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma / Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (RM HNSCC) Patients Who Are Resistant or Ineligible/Intolerant to Platinum-based Chemotherapy1
1, 2TerminatedTreatmentRecurrent Melanoma / Stage III Melanoma / Stage IV Melanoma1
2Active Not RecruitingTreatmentMelanoma1
2Active Not RecruitingTreatmentStage IIIC Melanoma / Stage IV Melanoma1
2CompletedSupportive CareDrug/Agent Toxicity by Tissue/Organ / Malignant Lymphomas1
2CompletedTreatmentExtraovarian Peritoneal Cancer / Fallopian Tube Carcinoma / Ovarian Epithelial Cancer1
2CompletedTreatmentGraft Versus Host Disease (GVHD) / Immune System Disorders1
2CompletedTreatmentLeukemia, Adult T-Cell1
2CompletedTreatmentLeukemia, Lymphocytic, Chronic1
2CompletedTreatmentLeukemias1
2CompletedTreatmentLeukemias / Systemic Mastocytosis1
2CompletedTreatmentLymphoma, B-Cell1
2CompletedTreatmentLymphoma, B-Cell / Lymphoma, Low-Grade / Non-Hodgkin's Lymphoma (NHL)1
2CompletedTreatmentMalignant Lymphomas3
2CompletedTreatmentMalignant Melanoma1
2CompletedTreatmentMelanoma (Skin) / Renal Cancers1
2CompletedTreatmentPeripheral T-Cell Lymphoma (PTCL)1
2Not Yet RecruitingOtherTransfusion-dependent Thalassemia (TDT) and Non-transfusion-dependent Thalassemia (NTDT)1
2TerminatedTreatmentLeukemia, Myelogenous, Acute1
2TerminatedTreatmentPancreatic Cancer Metastatic1
2Unknown StatusTreatmentCancer, Ovarian1
2Unknown StatusTreatmentLeukemias / Malignant Lymphomas1
2Unknown StatusTreatmentLymphoma, T-Cell, Peripheral1
2WithdrawnTreatmentAnaplastic Large-Cell Lymphoma1
4CompletedTreatmentLymphoma, T-Cell, Cutaneous1
4CompletedTreatmentLymphoma, T-Cell, Cutaneous / Mycosis Fungoides (MF) / Sezary Syndrome2
Not AvailableNo Longer AvailableNot AvailableCancers1
Not AvailableWithdrawnTreatmentMalignant Lymphomas1
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Injection, solutionIntravenous150 ug/mL
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.
PatentsNot Available
Properties
StateLiquid
Experimental Properties
PropertyValueSource
hydrophobicity-0.301Not Available
isoelectric point5.45Not Available
Taxonomy
DescriptionNot Available
KingdomOrganic Compounds
Super ClassOrganic Acids
ClassCarboxylic Acids and Derivatives
Sub ClassAmino Acids, Peptides, and Analogues
Direct ParentPeptides
Alternative ParentsNot Available
SubstituentsNot Available
Molecular FrameworkNot Available
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
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 autoreactive T cells.
Gene Name:
IL2RA
Uniprot ID:
P01589
Molecular Weight:
30818.915 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. 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:2786749 ]
  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:3124610 ]
  5. Duvic M, Talpur R: Optimizing denileukin diftitox (Ontak) therapy. Future Oncol. 2008 Aug;4(4):457-69. doi: 10.2217/14796694.4.4.457. [PubMed:18684057 ]
  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:17187516 ]
  7. 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
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
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. [PubMed:15811959 ]
  2. Foss F: Clinical experience with denileukin diftitox (ONTAK). Semin Oncol. 2006 Feb;33(1 Suppl 3):S11-6. [PubMed:16516670 ]
  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. [PubMed:18684057 ]
  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:17187516 ]
  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:
Interleukin-2 binding
Specific Function:
Common subunit for the receptors for a variety of interleukins.
Gene Name:
IL2RG
Uniprot ID:
P31785
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. [PubMed:15811959 ]
  2. Foss F: Clinical experience with denileukin diftitox (ONTAK). Semin Oncol. 2006 Feb;33(1 Suppl 3):S11-6. [PubMed:16516670 ]
  3. Foss FM: DAB(389)IL-2 (denileukin diftitox, ONTAK): a new fusion protein technology. Clin Lymphoma. 2000 Nov;1 Suppl 1:S27-31. [PubMed:11707860 ]
Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23