Designing the furin-cleavable linker in recombinant immunotoxins based on Pseudomonas exotoxin A.

ABSTRACT: Recombinant immunotoxins (RITs) are fusion proteins that join antibodies to protein toxins for targeted cell killing. RITs armed with Pseudomonas exotoxin A (PE) are undergoing clinical trials for the treatment of cancer. The current design of PE-based RITs joins an antibody fragment to the catalytic domain of PE using a polypeptide linker that is cleaved by the protease furin. Intracellular cleavage of native PE by furin is required for cytotoxicity, yet the PE cleavage site has been shown to be a poor furin substrate. Here we describe the rational design of more efficiently cleaved furin linkers in PE-based RITs, and experiments evaluating their effects on cleavage and cytotoxicity. We found that changes to the furin site could greatly influence both cleavage and cytotoxicity, but the tw

SUBMITTER: Weldon JE 

PROVIDER: S-EPMC7724502 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature