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.
Indications
Denileukin diftitox (DAB
389 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.
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.
