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Review
. 2014 Apr 17;123(16):2470-7.
doi: 10.1182/blood-2014-01-492256. Epub 2014 Feb 27.

Immunotoxins for leukemia

Alan S Wayne  1 , David J Fitzgerald, Robert J Kreitman, Ira Pastan
Affiliations
Review

Immunotoxins for leukemia

Alan S Wayne et al. Blood. .

Abstract

Unconjugated monoclonal antibodies that target hematopoietic differentiation antigens have been developed to treat hematologic malignancies. Although some of these have activity against chronic lymphocytic leukemia and hairy cell leukemia, in general, monoclonal antibodies have limited efficacy as single agents in the treatment of leukemia. To increase their potency, the binding domains of monoclonal antibodies can be attached to protein toxins. Such compounds, termed immunotoxins, are delivered to the interior of leukemia cells based on antibody specificity for cell surface target antigens. Recombinant immunotoxins have been shown to be highly cytotoxic to leukemic blasts in vitro, in xenograft model systems, and in early-phase clinical trials in humans. These agents will likely play an increasing role in the treatment of leukemia.

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Figures

Figure 1
Figure 1
Pathways of binding, internalization, and processing by immunotoxins leading to the killing of target cells. Shown are ricin-, Pseudomonas- and diphtheria-based immunotoxins. Immunotoxins bind the target antigen, are internalized via clathrin-coated pits, and are processed within endosomal compartments. Ricin and Pseudomonas toxin derivatives must traffic through the endoplasmic reticulum to the cytosol where they enzymatically inactivate protein synthesis. Pseudomonas exotoxin A ADP-ribosylates EF2, while ricin depurinates ribosomal RNA. Diphtheria-based toxins are internalized to endosomes where the A chain of the toxin translocates directly to the cytosol and ADP-ribosylates EF2. Cell death follows inhibition of protein synthesis. dgA: deglycosylated ricin A chain; EF2: elongation factor 2.
Figure 2
Figure 2
Molecular structures of Pseudomonas exotoxin (1IQK.pdb), diphtheria toxin (1TOX.pdb), and ricin toxin (2AAI.pdb). From left to right (blue to red), sequences are shown from the N-terminus to the C-terminus of each protein. To construct immunotoxins, the binding domain of each toxin is removed and replaced with an antibody or antibody fragment. The enzyme domains of PE, DT, and ricin are shown as either ADP-ribosylation or RNA N-glycosidase, as indicated. Middle domains for PE and DT are shown in yellow-green and include a furin processing site (white arrows): the furin site of DT is not ordered in the crystal structure so its approximate location is indicated. For DT, helical structures in the middle domain facilitate toxin translocation. The translocation activity of PE has not been definitively determined. Ricin apparently contains translocation sequences within the enzyme (blue) domain. The enzyme domain of ricin toxin is equivalent to deglycosylated ricin A chain. Intact ricin toxin contains tandem C-terminal binding modules (red).
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