Improving the <i>In Vivo</i> Efficacy of an Anti-Tac (CD25) Immunotoxin by <i>Pseudomonas</i> Exotoxin A Domain II Engineering.

ABSTRACT: Tac (CD25) is expressed on multiple hematologic malignancies and is a target for cancer therapies. LMB-2 is an extremely active anti-Tac recombinant immunotoxin composed of an Fv that binds to Tac and a 38-kDa fragment of Pseudomonas exotoxin A (PE38). Although LMB-2 has shown high cytotoxicity toward Tac-expressing cancer cells in clinical trials, its efficacy was hampered by the formation of anti-drug antibodies against the immunogenic bacterial toxin and by dose-limiting off-target toxicity. To reduce toxin immunogenicity and nonspecific toxicity, we introduced six point mutations into domain III that were previously shown to reduce T-cell immunogenicity and deleted domain II from the toxin, leaving only the 11aa furin cleavage site, which is required for cytotoxic activity. Alth

SUBMITTER: Kaplan G 

PROVIDER: S-EPMC6030476 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature