An anti‐CD5 immunotoxin for chronic lymphocytic leukemia: Enhancement of cytotoxicity with human serum albumin‐monensin

Abstract

Five patients with B-cell chronic lymphocytic leukemia (B-CLL) were treated with 6 courses of the anti-CD5 immunotoxin T101-ricin A chain (T101-RTA). Each course consisted of 8 bi-weekly infusions of T101-RTA (7 or 14 mg/m2). The immunotoxin was well tolerated in all cases with no major toxicities. Though saturation of circulating leukemic cell-associated target antigen was demonstrated by FACS analysis in all patients, no intact immunotoxin was detected in bone-marrow or lymph-node aspirates. Pharmacokinetic studies revealed rapid clearance of T101-RTA, with a half-life of 43 min. None of the patients developed detectable titers of antibody against either T101 murine antibody or ricin A chain. Clinical response was limited to a rapid and transient fall in WBC count lasting less than 24 hr, most likely secondary to the antibody portion of the conjugate. In vitro, fresh B-CLL cells were resistant to T101-RTA at concentrations up to 10(-8)M, while fresh malignant T-cells with a 10-fold increase in expression of CD5 antigen were sensitive. In the presence of the enhancing agent human serum albumin-monensin, fresh B-CLL cells were sensitive to T101-RTA, with an ID50 more than 2 logs below the maximal concentration of immunotoxin achieved in vivo. We conclude that T101-RTA is a potentially useful agent in the treatment of T-cell leukemias. In the presence of HSA-monensin, this spectrum of activity may be extended to B-CLL.

Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias

“…34,35 However, a number of our patient samples were relatively resistant to DTLIL3 suggesting that expression of the IL-3R on leukemic progenitors is variable. It is interesting to hypothesize that the sensitivity of some patient samples to the toxin may reflect the presence of an IL3-IL3R autocrine loop in these cells as has been previously described.…”

Antibody-Based Immunotoxins for the Treatment of Cancer

“…In another phase I trial, T101-RTA was administered in the presence of monensin, covalently linked to human serum albumin (HAS) for cytotoxicity enhancement. In this trial, conducted on 5 B-cell chronic lymphocytic leukemia (B-CLL) patients, no long term clinical effect was observed [126]. These trials were reported in 1989 and no further clinical trials were pursued.…”

Selective internalization of monoclonal antibodies by B‐cell chronic lymphocytic leukaemia cells

“…Some of the antigens targeted in the present study, such as CD5 (Hertler et al, 1989), CD19 (Grossbard & Fidias, 1995) and CD22 (Shan & Press, 1995) have been used as targets for immunotoxins for B-cell malignancies.…”