Denileukin diftitox
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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
- Clinical Trials
- Phase 0
- 1
- Phase 1
- 12
- Phase 2
- 31
- Phase 3
- 2
- Phase 4
- 3
- Mechanism of Action
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(CTCL),2,7 making it the first fusion protein cytotoxin approved to treat a human disease in the US.3 In 2014, it was withdrawn voluntarily from the market due to manufacturing issues; however, the biologics license application (BLA) for denileukin diftitox was resubmitted, and it was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 ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Cutaneous t-cell lymphoma recurrent •••••••••••• ••••• ••••••••• Treatment of Refractory cutaneous t-cell lymphoma stage i •••••••••••• ••••• •• ••••• ••• ••••• •••••••• ••••••• Treatment of Refractory cutaneous t-cell lymphoma stage ii •••••••••••• ••••• •• ••••• ••• ••••• •••••••• ••••••• Treatment of Refractory cutaneous t-cell lymphoma stage iii •••••••••••• ••••• •• ••••• ••• ••••• •••••••• ••••••• Treatment of Relapsed cutaneous t-cell lymphoma stage i •••••••••••• ••••• •• ••••• ••• ••••• •••••••• ••••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- 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
Target Actions Organism AInterleukin-2 receptor subunit alpha ligandHumans AInterleukin-2 receptor subunit beta ligandHumans - 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
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- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAmbroxol The risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Ambroxol. Articaine The risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Articaine. Benzocaine The risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Benzocaine. Benzyl alcohol The risk or severity of methemoglobinemia can be increased when Denileukin diftitox is combined with Benzyl alcohol. Bupivacaine The 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 regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ontak Injection, solution 150 ug/1mL Intravenous Eisai Limited 2013-11-01 2013-11-01 US
Categories
- ATC Codes
- L01XX29 — Denileukin diftitox
- Drug Categories
- ADP Ribose Transferases
- Amino Acids, Peptides, and Proteins
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Bacterial Toxins
- Biological Factors
- Cancer immunotherapy
- CD25-directed Cytotoxin
- Enzymes and Coenzymes
- Immunotherapy
- Intercellular Signaling Peptides and Proteins
- Interleukins
- Narrow Therapeutic Index Drugs
- Peptides
- Proteins
- Recombinant Fusion Proteins
- Recombinant Proteins
- Toxins, Biological
- 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
- 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]
- Manoukian G, Hagemeister F: Denileukin diftitox: a novel immunotoxin. Expert Opin Biol Ther. 2009 Nov;9(11):1445-51. doi: 10.1517/14712590903348135. [Article]
- 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]
- 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]
- FDA Approved Drug Products: LYMPHIR (denileukin diftitox-cxdl) for injection, for intravenous use [Link]
- FDA Approved Products: ONTAK (denileukin diftitox) injection, for intravenous use (February 2020) [Link]
- Targeted Oncology: FDA Approves Improved Denileukin Diftitox in Cutaneous T-Cell Lymphoma [Link]
- External Links
- UniProt
- P00587
- Genbank
- V01536
- PubChem Substance
- 46506950
- 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 Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Cutaneous T-Cell Lymphoma (CTCL) / Peripheral T-Cell Lymphoma (PTCL) 1 somestatus stop reason just information to hide Not Available No Longer Available Not Available Cancer 1 somestatus stop reason just information to hide Not Available Withdrawn Treatment Lymphoma 1 somestatus stop reason just information to hide 4 Completed Treatment Cutaneous T-Cell Lymphoma (CTCL) 1 somestatus stop reason just information to hide 4 Completed Treatment Cutaneous T-Cell Lymphoma (CTCL) / Mycosis Fungoides (MF) / Sezary Syndrome 2 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Eisai Inc.
- Hollister-Stier Laboratories LLC
- Ligand Pharmaceuticals Inc.
- Dosage Forms
Form Route Strength Injection, solution Intravenous 150 ug/1mL - Prices
Unit description Cost Unit Ontak 150 mcg/ml vial 878.4USD ml DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
Property Value Source hydrophobicity -0.301 Not Available isoelectric point 5.45 Not Available
Targets
- 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
- 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]
- 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]
- 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]
- 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]
- 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
- 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]
- Foss F: Clinical experience with denileukin diftitox (ONTAK). Semin Oncol. 2006 Feb;33(1 Suppl 3):S11-6. [Article]
- 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]
- 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]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- 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