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Immunotoxins

Overview

Immunotoxins use MAb technology conjugated to natural toxins. Monoclonal antibodies are well established in cancer therapy. Immunotoxins have a lack of encouraging data in non-Hodgkin’s lymphoma, but their activity in blood-based tumors versus solid tumors may prove more efficacious.

Mechanism Of Action

Immunotoxins comprise peptides, usually an antibody or growth factor, which are linked to toxins such as diphtheria toxin, Pseudomonas exotoxin, or ricin. This “magic bullet” mechanism is designed to target the toxic moiety to a specific cell by binding the growth factor/antibody portion of the immunotoxin to its cell surface receptor. Upon internalization, the toxin is cleaved into an active form and causes cell death.

Denileukin Diftitox

Ligand Pharmaceuticals is developing denileukin diftitox (Ontak) for the treatment of chronic lymphocytic leukemia. Phase II trials are underway in the United States. This agent has already been launched in the United States and preregis-tered in Western Europe for the treatment of cutaneous T-cell lymphoma.

Denileukin diftitox is an interleukin-2 (IL-2) diphtheria toxin fusion protein; it is designed to direct the cytocidal action of diphtheria toxin to cells that express the IL-2 receptor. The human IL-2 receptor exists in three forms: low (CD25), intermediate (CD122/CD132), and high (CD25/CD122/CD132) affinity, the last of which is expressed on activated T and B lymphocytes and activated macrophages.

Researchers presented data from a Phase II trial in which heavily pretreated, fludarabine-refractory chronic lymphocytic leukemia patients received denileukin diftitox at a dose of 18 µg/kg/day or 9 µg/kg/day (if older than 70) intravenously for 5 days every 21 days. The mean age of patients enrolled in this study was 61.8 years and included 14 males and 4 females with Rai stages I (n = 2), II (n = 6), and IV (n = 10) who had received a mean of 4.5 prior treatments. Eleven out of 12 patients who received three or more courses of denileukin diftitox showed a reduced chronic lymphocytic leukemia cell count, and 6 of the 11 showed a >95% reduction. Seven of 12 patients showed a reduction in all lymph node diameters, with 1 patient showing 60% and another 80% shrinkage. Pre- and post-bone marrow biopsies performed on 11 patients showed a reduction in chronic lymphocytic leukemia marrow index; 7/11 had>50% reduction, including >98% in 3 patients.

In the study, denileukin diftitox produced 2/12 (17%) PRs and 7/12 (58%) minimal responses. Progression-free intervals ranged from 1 to more than 19 months. Toxicities were mild to moderate and included asymptomatic transient transaminasemia, fever, hypoalbuminemia, nausea, vomiting, elevated creatinine kinase, and vascular leak syndrome. The results suggest this agent has some biologic activity in this difficult-to-treat group of patients.

Previous published data have reported that immunotoxins directed against CD25 are more effective in treating malignancies where the expression of surface CD25 is high, such as in hairy-cell leukemia. Research has determined that chronic lymphocytic leukemia cells can be sensitized to CD25-directed immunotoxins by treating them with an agent that upregulates CD25 expression. A follow-up study is investigating denileukin diftitox therapy in combination with bexarotene (Ligand’s Tagretin), a retinoid X receptor (RXR) selective agonist known to upregulate IL-2 receptor expression.

Another study of denileukin diftitox therapy also presented data on a small number of heavily pretreated fludarabine-refractory patients. Their median age was 63, and patients had received three to eight prior therapies. Of the five evaluable patients, the median number of denileukin diftitox cycles received was three. Therapy was stopped after one cycle because of grade 4 hepatitis, diarrhea, and disseminated herpes simplex with fatal pneumonia and after two cycles because of grade 4 vascular leak with microangiopathy/cardiac tamponade or lack of efficacy. Other toxicities included grade 1 and 2 fatigue and myalgias; grade 4 anorexia; and grade 1, 2, and 4 raised liver function. Two of the five patients achieved a PR, both of which were ongoing at 12+ months, and two achieved minor responses (1 month and ongoing at 6+ months). CD25-positive and -negative patients were treated, and PR was observed in both groups. Furthermore, therapy with denileukin diftitox resulted in reduced lymphocytosis (median pre = 55 and post = 3.7) and a more normalized range of hemoglobin, neutrophils, and platelets.

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