Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

To target tumor cells that overexpress the urokinase plasminogen activator system, the furin cleavage site in anthrax PA protein was replaced by sequences that are specifically cleaved by uPA. The modified PA was then combined with FP59, a fusion between the ADP-ribosylation domain of Pseudomonas exotoxin A and amino acids 1-254 of LF (see above). In the presence of pro-uPA and plasminogen, the recombinant complex (PrAg-U2 + FP59) was demonstrated to be activated selectively on the surface of uPAR-expressing tumor cells from a broad range of human cancers of different origins, and ultimately resulted in specific tumor cell eradication [425, 427] . Subsequent in vivo studies have demonstrated efficient suppression of different murine tumors growth and eradication of established tumors with limited toxicity to normal tissue upon local and systemic administration of the complex [426, 428] . 100% tumor regression and 30% complete histologic remission after systemic administration of tolerated doses of PrAg-U2+FP59 were documented in an in vivo athymic nude mouse model of human non-small cell lung cancer (NSCLC) [429] .