ABSTRACT
The principal objective in engineering a chimeric immunotoxin is to replace the native toxin binding specificity without effecting the membrane translocation and cytosolic release or the toxin's ability to inactivate protein synthesis. The efficiency of translocation of an immunotoxin across the appropriate membrane and release into the cytosol is an important step; thus, it should be considered in the design and testing of a chimeric immunotoxin. A number of successful chimeric immunotoxins have been produced in which the cell-binding portion of Pseudomonas exotoxin or diphtheria toxin has been replaced, leaving the cytotoxic and translocation domains intact. In the design of a ricin-derived chimeric immunotoxin, one would like to include portions of the hydrophobic interface between the A and B chains of ricin to facilitate membrane translocation while eliminating the galactose-binding activity. Enhancing the cell-binding specificity or the membrane-translocation activity of an immunotoxin is likely to result in an enhanced toxicity to the target cells.
