Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor

Abstract

DAB486IL-2 is a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with human interleukin-2 (IL-2). It selectively binds and intoxicates only cells that bear the high-affinity receptor for IL-2. In the first clinical trial of a genetically engineered ligand fusion-toxin, we have treated 18 patients with chemotherapy-resistant IL-2 receptor expressing hematologic malignancies with escalating doses of DAB486IL-2. The maximal tolerated dose of a daily intravenous bolus of DAB486IL-2 was 0.1 mg/kg per day for 10 doses, established by asymptomatic, reversible elevations of hepatic transaminases without changes in other tests of liver function. Other mild reversible side effects noted were rash, nausea, elevated creatinine, chest tightness, and fever. Pharmacokinetic analysis showed a monophasic clearance of 5.8 +/- 0.7 minutes with peak levels of 3,549 +/- 1,041 mg/mL at the 0.1 mg/kg dose. Approximately 50% of patients developed an antibody response to diphtheria toxin or DAB486IL-2. The presence of such antibodies did not preclude patients from experiencing an antitumor response as four of the six patients with antitumor effect had detectable antibody titers. Although this was a phase I trial designed to define the safety of DAB486IL-2, remissions were observed in three patients lasting from 5 to over 18 months. The ability to achieve significant tumor reductions in this group of heavily treated patients is encouraging and suggests additional trials are warranted in hematologic malignancies.

Immunotoxins for targeted cancer therapy

“…62 , 123 Clinical trials showed some effi cacy with DAB 486 IL-2 in hematologic malignancies with dose-limiting transaminase elevations. [124][125][126] A new fusion toxin was created by removing amino acids 389 to 485, and it was found that DAB 389 IL-2, also called denileukin diftitox or Ontak ( Figure 2 ), had improved half-life, cytotoxicity, and tolerance in animals. 65 In phase I testing there were 5 complete remissions (CRs) and 8 partial responses (PRs) in 35 patients with CTCL, and 1 CR and 2 PRs out of 17 patients with NHL.…”

Targeting diphtheria toxin to growth factor receptors

“…A series of phase I/II clinical studies were developed to determine the safety, tolerability, and pharma-cokinetics of DAB 486 IL-2 in patients with refractory hematologic malignancies. [55][56][57] These early studies employed DAB 486 IL-2 as the experimental therapeutic in order to establish the 'proof of principal' that the diphtheria toxin-based fusion toxins would show some degree of efficacy in the treatment of human disease. In fact, several of these clinical studies were initiated prior to the isolation and characterization of the more potent DAB 389 IL-2 form of the fusion toxin.…”

Targeted Fc2′-3-PE40 chimeric protein abolishes passive cutaneous anaphylaxis in mice

“…As the chimeric protein is not of human origin, its prolonged administration can result in the generation of antibodies. However, using other chimeric proteins, based on diphtheria toxin, in clinical trials it was reported that responses could be obtained despite the presence of antibody [23].…”