denileukin diftitox

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Ligands
denileukin diftitox

GtoPdb Ligand ID: 7044

Synonyms: DAB389 IL2 | denileukin diftitox-cxdl | LY 335348 | Lymphir® | Ontak®

denileukin diftitox is an approved drug (FDA (1999))

Compound class: Peptide

Comment: Denileukin diftitox is an anti-cancer immunotherapy drug that was designed to target and eradicate malignant (IL-2 receptor-expressing) T cells. It is a recombinant protein containing peptide sequences of both interleukin-2 and diphtheria toxin [1,5]. It simultaneously directly kills IL-2R expressing tumour cells and promotes depletion of host Treg cells which enhances the immune response

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Summary of Clinical Use
Denileukin diftitox was originally authorised to treat malignant leukemias and lymphomas which express cell surface IL-2 receptors. In August 2024, the FDA expanded approval to include treatment of relapsed/refractory cutaneous T-cell lymphoma.

Summary of Clinical Use

Denileukin diftitox was originally authorised to treat malignant leukemias and lymphomas which express cell surface IL-2 receptors. In August 2024, the FDA expanded approval to include treatment of relapsed/refractory cutaneous T-cell lymphoma.

Mechanism Of Action and Pharmacodynamic Effects
The IL-2 sequence of this dual domain drug binds to cell surface IL-2 receptors and upon internalisation via receptor-mediated endocytosis and endocytic processing, the diptheria toxin is liberated and is able to act on its intracellular target, EEF2 (eukaryotic translation elongation factor 2) [1], effectively shutting down protein synthesis in the cell. Diptheria toxin belongs to a diphthamide-specific class of ADP-ribose transferases, and is able to inactvate EEF2 by catalysing the transfer of NAD⁺ to the diphthamide residue (a posttranslationally modified histidine residue, PubChem CID 6438375) contained in this protein. Mutation of this dipthamide resudue renders EEF2 resistant to diptheria toxin [2].

Mechanism Of Action and Pharmacodynamic Effects

The IL-2 sequence of this dual domain drug binds to cell surface IL-2 receptors and upon internalisation via receptor-mediated endocytosis and endocytic processing, the diptheria toxin is liberated and is able to act on its intracellular target, EEF2 (eukaryotic translation elongation factor 2) [1], effectively shutting down protein synthesis in the cell. Diptheria toxin belongs to a diphthamide-specific class of ADP-ribose transferases, and is able to inactvate EEF2 by catalysing the transfer of NAD⁺ to the diphthamide residue (a posttranslationally modified histidine residue, PubChem CID 6438375) contained in this protein. Mutation of this dipthamide resudue renders EEF2 resistant to diptheria toxin [2].

Clinical Trials
Clinical Trial ID	Title	Type	Source	Comment	References
NCT00254332	Effect of Denileukin Diftitox on Immune System in CTCL Patients	Observational	FDA Office of Orphan Products Development
NCT00211198	Study of ONTAK® to Treat Cutaneous T-Cell Lymphoma (CTCL)	Phase 4 Interventional	Eisai Inc.
NCT01871727	A Trial of E7777 in Persistent and Recurrent Cutaneous T-Cell Lymphoma	Phase 3 Interventional	Eisai Inc.		3
NCT00000189	Gepirone vs Placebo in Treatment of Cocaine Dependence - 3	Phase 2 Interventional	University of Pennsylvania		4