Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders

Abstract

Denileukin diftitox (Ontak^®) represents an example of a fused molecule that targets cells bearing high affinity interleukin-2 receptors internalized via receptor-mediated endocytosis in an acidified vesicle. Denileukin diftitox is proteolytically cleaved within the endosome liberating the enzymatically active portion of the diphtheria toxin, the A fragment. Diphtheria toxin fragment A is released into the cytosol inhibiting the protein synthesis through the ADP-ribosylation of the elongation factor-2, and leading to cell death. This review focuses on the clinical trials that led to the FDA approval of the drug for cutaneous T cell lymphoma in the US, and investigational studies demonstrating drug-activity against B and T-cell non-Hodgkin’s lymphoma, chronic lymphocytic lymphoma and acute graft versus disease within allogeneic hematopoietic stem cell transplant.

Keywords::

• chronic lymphocytic leukemia
• cutaneous T cell lymphoma
• denileukin diftitox
• graft-versus-host disease
• interleukin-2 receptor
• non-Hodgkin’s lymphoma
• Ontak^®
• targeted therapy