Immunotoxin

denileukin diftitox Denileukin diftitox (ontak) is an immunotoxin made from the genetic recombination of IL-2 and the catalytically active fragment of diphtheria toxin. The human IL-2 receptor (IL-2R) is not expressed on resting T cells, but is constitutively expressed on malignant lymphocytes of both T-cell and B-cell origin. Denileukin diftitox is FDA-approved for the treatment of recurrent/refractory cutaneous T-cell lymphomas. Denileukin diftitox is being evaluated in patients with CD25-negative tumors and modulators of CD25 expression are being combined in an attempt to increase response rates. Bexarotene increases the level of CD25 expression on malignant T cells and provides a rationale for combining these agents.

Systemic exposure to denileukin diftitox is variable but proportional to dose. It has a distribution t122 of 2-5 minutes with a terminal t122 of ~70 minutes. Immunologic reactivity to denileukin difti-tox can be detected in virtually all patients after treatment but does not preclude clinical benefit with continued treatment. Denileukin diftitox clearance in later cycles of treatment is accelerated by two- to threefold as a result of development of antibodies, but serum levels are greater than required to produce cell death in IL-2R-expressing cell lines (1-10 ng2mLfor more than 90 minutes). Patients with a history of hypersensitivity reactions to diphtheria toxin or IL-2 should not be treated. Significant toxicities associated with denileukin diftitox are acute hypersensitivity reactions, a vascular leak syndrome, and constitutional toxicities; glucocorticoid premedication significantly decreases toxicity.

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