Denileukin diftitox

Overview

Description
A medication used to treat a rare form of blood cancer in adults who were previously treated.
Description
A medication used to treat a rare form of blood cancer in adults who were previously treated.
DrugBank ID
DB00004
Type
Biotech
US Approved
YES
Other Approved
NO
Clinical Trials
Phase 0
1
Phase 1
12
Phase 2
31
Phase 3
2
Phase 4
3
Therapeutic Categories
  • CD25-directed Cytotoxin

Identification

Summary

Denileukin diftitox is an IL2-receptor-directed cytotoxin indicated for the treatment of relapsed or refractory Stage I to III cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

Generic Name
Denileukin diftitox
DrugBank Accession Number
DB00004
Background

Denileukin diftitox is an IL2-receptor-directed cytotoxin, is a recombinant DNA-derived fusion protein composed of the amino acid sequences for diphtheria toxin fragments A and B (Met1-Thr387)-His and the sequence for human interleukin-2 (IL-2; Ala1-Thr133).5 It is designed to deliver diphtheria toxin into IL-2 receptor-expressing cancer cells to cause cell death.4,5

Denileukin diftitox was originally approved by the FDA in 1999 for the treatment of cutaneous T-cell lymphoma (CTCL),2,7 making it the first fusion protein cytotoxin approved to treat a human disease in the US.3 In 2014, it was withdrawn voluntarily from the market due to manufacturing issues; however, the biologics license application (BLA) for denileukin diftitox was resubmitted, and it was approved on August 8, 2024.7

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Fusion proteins
Protein Structure
Protein Chemical Formula
C2560H4042N678O799S17
Protein Average Weight
58000.0 Da (approximate)
Sequences
Not Available
Synonyms
  • DAB(SUB 389)IL2
  • Denileukin
  • Denileukin diftitox
  • Interleukin-2/diptheria toxin fusion protein
  • N-L-METHIONYL-387-L-HISTIDINE-388-L-ALANINE-1-388-TOXIN (CORYNEBACTERIUM DIPHTHERIAE STRAIN C7) (388->2') PROTEIN WITH 2-133-INTERLEUKIN 2 (HUMAN CLONE PTIL2-21A)
  • N-MET-187-HIS-388-ALA-1-388-TOXIN (CORYNEBACTERIUM DIPHTHERIAE C7) WITH 1-133-INTERLEUKIN 2
External IDs
  • DAB-389IL2
  • DAB389 IL2
  • DAB389IL2
  • E-7272
  • E-7777
  • E7272
  • E7777
  • LY 335348
  • LY-335348
  • LY335348

Pharmacology

Indication

Denileukin diftitox was previously indicated for the treatment of adult patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor.6 It is also indicated for the treatment of adult patients with relapsed or refractory Stage I-III CTCL after at least one prior systemic therapy.5

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofCutaneous t-cell lymphoma recurrent••••••••••••••••••••••••••
Treatment ofRefractory cutaneous t-cell lymphoma stage i••••••••••••••••••• ••••• ••• ••••• •••••••• •••••••
Treatment ofRefractory cutaneous t-cell lymphoma stage ii••••••••••••••••••• ••••• ••• ••••• •••••••• •••••••
Treatment ofRefractory cutaneous t-cell lymphoma stage iii••••••••••••••••••• ••••• ••• ••••• •••••••• •••••••
Treatment ofRelapsed cutaneous t-cell lymphoma stage i••••••••••••••••••• ••••• ••• ••••• •••••••• •••••••
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
Pharmacodynamics

Denileukin diftitox is an anticancer drug with cytocidal actions on cancer cells.5 Denileukin diftitox demonstrated the ability to deplete immunosuppressive regulatory T lymphocytes (Tregs) and antitumor activity through direct cytocidal action on IL-2R-expressing tumours.5

Mechanism of action

Denileukin diftitox is a fusion protein composed of truncated diphtheria toxin (DT), which is a cytocidal moiety, and the full-length sequence of interleukin-2 (IL-2), which acts as a ligand for the IL-2 receptor.3 Denileukin diftitox is reported to bind to a high- or intermediate-affinity receptor.3 Once the drug molecule binds to the IL-2 receptor, denileukin diftitox is internalized via receptor-mediated endocytosis in an acidified vesicle.1,3 After uptake into the cell, denileukin diftitox is proteolytically cleaved within the endosomes to release the enzymatically active portion of the DT. DT is translocated across the endosomal membrane into the cytosol to inhibit protein synthesis via ADP-ribosylation of elongation factor-2, ultimately resulting in cell death. The fragment of DT is translocated across the endosomal membrane into the cytosol where it inhibits protein synthesis via ADP-ribosylation of elongation factor-2, resulting in cell death.3,5

TargetActionsOrganism
AInterleukin-2 receptor subunit alpha
ligand
Humans
AInterleukin-2 receptor subunit beta
ligand
Humans
Absorption

Following a single dose of denileukin diftitox 9 mcg/kg via one-hour infusion in patients with CTCL, the geometric mean (coefficient of variation [CV]%) maximum serum concentration (Cmax) was 94.4 ng/mL (77%) and area under the concentration over time curve (AUC0-inf) was 20700 ng x min/L (60%) on the first day of the first administration cycle. There is no accumulation after repeated daily dosing.5

Volume of distribution

The geometric mean (CV%) volume of distribution of denileukin diftitox is 5.0 L (43%) on the first day of the first administration cycle.5

Protein binding

Not Available

Metabolism

Denileukin diftitox is expected to be metabolized into small peptides by catabolic pathways.5

Route of elimination

Not Available

Half-life

The arithmetic mean (CV%) denileukin diftitox terminal half-life is 112 minutes (31%) on the first day of the first cycle.5

Clearance

The geometric mean (CV%) clearance is 36.5 mL/min (73%) after the first dose of denileukin diftitox at the recommended dose level.5

Adverse Effects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
Toxicity

There is limited information regarding the acute toxicity (LD50) and overdose of denileukin diftitox.

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
AmbroxolThe risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Ambroxol.
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.
Food Interactions
No interactions found.

Products

Drug product information from 10+ global regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
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. Manoukian G, Hagemeister F: Denileukin diftitox: a novel immunotoxin. Expert Opin Biol Ther. 2009 Nov;9(11):1445-51. doi: 10.1517/14712590903348135. [Article]
  3. Lansigan F, Stearns DM, Foss F: Role of denileukin diftitox in the treatment of persistent or recurrent cutaneous T-cell lymphoma. Cancer Manag Res. 2010 Feb 5;2:53-9. doi: 10.2147/cmar.s5009. [Article]
  4. Prince HM, Martin AG, Olsen EA, Fivenson DP, Duvic M: Denileukin diftitox for the treatment of CD25 low-expression mycosis fungoides and Sezary syndrome. Leuk Lymphoma. 2013 Jan;54(1):69-75. doi: 10.3109/10428194.2012.706286. Epub 2012 Sep 14. [Article]
  5. FDA Approved Drug Products: LYMPHIR (denileukin diftitox-cxdl) for injection, for intravenous use [Link]
  6. FDA Approved Products: ONTAK (denileukin diftitox) injection, for intravenous use (February 2020) [Link]
  7. Targeted Oncology: FDA Approves Improved Denileukin Diftitox in Cutaneous T-Cell Lymphoma [Link]
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

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableCompletedNot AvailableCutaneous T-Cell Lymphoma (CTCL) / Peripheral T-Cell Lymphoma (PTCL)1somestatusstop reasonjust information to hide
Not AvailableNo Longer AvailableNot AvailableCancer1somestatusstop reasonjust information to hide
Not AvailableWithdrawnTreatmentLymphoma1somestatusstop reasonjust information to hide
4CompletedTreatmentCutaneous T-Cell Lymphoma (CTCL)1somestatusstop reasonjust information to hide
4CompletedTreatmentCutaneous T-Cell Lymphoma (CTCL) / Mycosis Fungoides (MF) / Sezary Syndrome2somestatusstop reasonjust information to hide

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

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
General 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
Specific Function
interleukin-2 binding
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]
  5. FDA Approved Drug Products: LYMPHIR (denileukin diftitox-cxdl) for injection, for intravenous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
General Function
Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2. Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770, PubMed:31040185)
Specific Function
coreceptor activity
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]
  6. FDA Approved Drug Products: LYMPHIR (denileukin diftitox-cxdl) for injection, for intravenous use [Link]

Drug created at June 13, 2005 13:24 / Updated at September 05, 2024 06:29