Immunotoxin therapy of hematological malignancies.

everal years have passed since the potential for unconjugated monoclonal antibodies (mAbs) to selectively target malignant cells was first described. Although the concept behind serotherapy is theoretically simple, the overall clinical results in these studies have often been disappointing and numerous obstacles have emerged due to the difficulty in penetrating tumor masses, the limited inherent cytotoxic activity of many mAbs, and the large amount of antibody often required for therapeutic efficacy with consequent prohibitive costs. 1,2 Over the last decade, progress have been made in rendering native mAbs more effective by coupling them to drugs, toxic agents or radionuclides. In this review we will limit our consideration to toxin-antibody conjugates and their possible application in the treatment of hematological malignancies. Immunotoxins (ITs) are synthetic hybrid molecules consisting of a highly potent toxin moiety linked to a mAb selectively directed toward specific cell targets. 3-8 Essential prerequisites for the clinical use of ITs are: a) a high specificity and affinity of the Ab component for the target molecule, which should be consistently expressed on neoplastic cells and have minimal distribution in normal human tissues; b) a high density of the target antigen on the surface of neoplastic cells; c) the potential for the IT to be internalized after anti-gen binding and routed to the appropriate intracellular compartment for translocation of the attached toxin to the apparatus where it exerts its effect. Efficient ITs have been prepared using several toxins of plant or bacterial origin (Table 1). This paper will review only the ribosome-inactivat-ing proteins from plants (RIPs). 9 These molecules exist in nature in two forms: type 1 and 2 RIPs. Type 2 RIPs are holotoxins containing two polypeptide chains, namely A and B (Table 1). The A chain is the enzymatically active one and is linked, through a disulphide bond, to a sugar-binding B-chain that recognizes the galactosyl-terminated receptors present on the surface of most mammalian cells and promotes the translocation of the A chain into the cytoplasm. Among type 2 RIPs, ricin has been the one most widely used in preclinical and clinical studies. Predictably, ITs containing native ricin and other type 2 RIPs lack specificity since thay bind not only to target cells, but virtually to any other cell via the B chain. This problem has been successfully circumvented by altering or deleting the binding domain through two different approaches: 1) by separating the functionally active A chain …