denileukin diftitox

Description

Denileukin diftitox was first launched as Ontak in the US for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor. Denileukin diftitox is a diphtheria toxin fragment A - fragment B genetically fused to a human interleukin-2 (IL-2) fragment. In vivo the IL-2 fragment seeks out activated T-cells through their IL-2 receptor. After binding, the fusion protein enters the cell by endocytosis and the toxin kills the cell by inhibiting protein synthesis. Affinity, potency and half-life of this product were greatly improved by deletion of 97 amino acids on the C-terminus of the diphtheria toxin. It is, to date, one of the most extensively evaluated fusion proteins that combine a toxin with a targeting molecule. The fusion protein is expressed in Eschefichia coli strain and purified by a series of diafiltration steps and finally by reverse phase chromatography. Antibodies against Ontak were present in 92% of patients after two courses but there was no relationship between the presence of antibodies and the likelihood of responding to the drug. In a randomized, double blind, phase III trial in 71 patients with recurrent CTCL, injection for 5 days every three weeks over 8 courses produced >50% reduction in tumor burden lasting up to 4 months in 30% of patients. Other potential indications for Denileukin diftitox are for treatment of psoriasis, HIV infection, atopic dermatitis, alopecia aerata, multiple sclerosis and inflammatory bowel disease.

Originator

Ligand (US)

Indications

Denileukin diftitox (DAB₃₈₉ IL-2, Ontak) is indicated for treatment of patients with cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor. Denileukin diftitox is a recombinant fusion protein composed of IL-2 amino acid sequences joined to sequences of diphtheria toxin. The drug targets and destroys cells expressing the highaffinity (CD25/CD122/CD132) IL-2 receptor, including the malignant cells of cutaneous T-cell lymphoma.

brand name

Ontak

General Description

Denileukin diftitox, recombinant, Ontak, is an example of adrug that acts like a Trojan horse. One part of the molecule isinvolved in recognition and binds selectively with the diseasedcell, and a highly toxic second part of the molecule effectsa kill. Denileukin diftitox is a fusion protein expressedby a recombinant strain of E. coli.
The diphtheriatoxin inhibits cellular protein synthesis and the cells die.Malignant cells in certain leukemias and lymphomas, includingcutaneous T-cell lymphoma, express the high-affinityIL-2 receptor on their cell surfaces. It is these cells thatdenileukin diftitox targets.Denileukin diftitox is indicated for the treatment of persistentor recurrent cutaneous T-cell lymphoma whose malignantcells express the CD25 component of the IL-2 receptor.Denileukin diftitox is supplied as a frozen solution inwater for injection. It should be stored at 10°C or colder.It is suggested that the vials be thawed in a refrigerator at2°C to 8°C for less than 24 hours or at room temperature for1 to 2 hours. Prepared solutions should be used within6 hours. The drug is administered by IV infusion from a bagor through a syringe pump.

Pharmacology

The half-life of the drug is approximately 75 minutes after intravenous infusion. Antibodies directed against the diphtheria domain decrease mean systemic exposure by approximately 75%.Approximately 85% of patients develop such antibodies after a single course of treatment, and nearly all do after 3 cycles.

Clinical Use

rDNA-derived fusion protein consisting of diphtheria toxin fragments A and B as well as interleukin-2. Used in treating cutaneous T-cell lymphoma.

Side effects

Most patients using denileukin diftitox have flulike symptoms (fever, chills, myalgias, nausea, diarrhea) within a few hours to days of treatment. Another common adverse effect is an immediate hypersensitivity syndrome in which hypotension, back pain, dyspnea, chest pain or tightness, and rash may occur. Other notable side effects include a vascular leak syndrome (edema, hypoalbuminemia, hypotension), infections, and elevations of transaminases.

Raw materials

Preparation Products