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Advances in the Development of Anti-CD22 Immunotoxins Containing Pseudomonas Exotoxin for Treatment of Hematologic Malignancies

Abstract

Robert Lechleider and Ira Pastan

Immunotoxins composed of monoclonal antibodies linked to bacterial or plant protein toxins have been studied during the past 30 years as a potential targeted therapy for cancer. A series of refinements in the design of immunotoxins containing the bacterial toxin Pseudomonas exotoxin A (PE) led to the development of the current smaller, more selective, and more stable recombinant immunotoxins that are composed of a truncated form of PE fused to the variable domain of a monoclonal antibody. Immunotoxins targeting CD22, an antigen commonly expressed on B-cell malignancies, including BL22 (also known as CAT-3888) and its improved, higher affinity derivative, moxetumomab pasudotox (also known as HA22 or CAT-8015) are being evaluated in patients with hematologic malignancies. BL22 induced complete remissions in the majority of patients with chemoresistant hairy cell leukemia (HCL) during phase 1 and 2 studies, and showed promising antitumor activity in patients with chronic lymphocytic leukemia (CLL). Moxetumomab pasudotox is currently undergoing phase 1 testing in refractory HCL, as well as in CLL, non-Hodgkin lymphoma, and pediatric acute lymphoblastic leukemia (ALL). Thus far, clinical activity has been observed in approximately 80% of adult patients with HCL and complete remissions have been reported in 25% of children with ALL. No dose-limiting toxicities have been reported in the adult study in patients with HCL or in patients in the pediatric study who also received dexamethasone.