Immunotoxins in the Treatment of Hematologic Malignancies

Immunotoxins, composed of protein toxins connected to cell binding ligands including monoclonal antibodies and growth factors, have been developed for several decades to target hematologic malignancies. Protein toxins from either plants or bacteria are extremely potent based on their enzymatic inhibition of protein synthesis and induction of apoptosis. Plant toxins, particularly ricin, are useful for chemically conjugating to monoclonal antibodies, and have shown clinical activity in several types of lymphoma and leukemia. Their dose is generally limited by vascular leak syndrome. Bacterial toxins have been used to produce single chain fusions with either growth factors or recombinant antibody fragments. These agents are smaller in size (55-65 kDa) and exit the bloodstream much more rapidly than the chemical conjugates, and generally do not cause severe vascular leak syndrome. The only approved drug containing a protein toxin is denileukin diftitox, a fusion of human interleukin 2 with truncated diphtheria toxin. Denileukin diftitox has shown efficacy in cutaneous T-cell lymphoma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma. Recombinant immunotoxin BL22 is an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin; it induces complete remissions in a high percentage of patients with chemoresistant hairy cell leukemia. The anti-CD25 recombinant immunotoxin LMB-2 is active in several CD25+ hematologic malignancies. Several other recombinant immunotoxins are undergoing preclinical development for other target antigens expressed on hematologic malignancies.