Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

The most common toxicities in patients treated with immunotoxins are vascular leak syndrome (VLS) and hepatotoxicity, caused by non-specific binding of the toxic or the targeting moiety of the immunotoxin to endothelial and hepatic cells, respectively (for review, see [11, 520, 521] ). Regarding this issue, Baluna et al have found that sequences of three amino acids in ricin toxin (and in other proteins associated with vascular leak syndrome) might cause endothelial damage by a mechanism involving disruption of integrins, independently of the "classical" cell killing mediated by the toxin's enzymatic activity [522] . By screening a panel of recombinant ricin A chains with mutations in this sequence or in amino acids flanking it in the three-dimensional structure, a mutant form of RTA showing diminished VLS in mice was isolated [523, 524] .