HER2-specific recombinant immunotoxin 4D5scFv-PE40 passes through retrograde trafficking route and forces cells to enter apoptosis
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Evgeniya Sokolova1,3, Evgeniy Guryev1, Andrey Yudintsev1, Vladimir Vodeneev1, Sergey Deyev1,3, Irina Balalaeva1,2,3
1Institute of Biology and Biomedicine, Lobachevsky University, Nizhny Novgorod 603950, Russia
2Institute of Regenerative Medicine, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
3Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia
Irina Balalaeva, email: [email protected]
Keywords: targeted therapy, HER2, 4D5scFv, Pseudomonas aeruginosa exotoxin A, PE40
Received: September 23, 2016 Accepted: February 06, 2017 Published: March 02, 2017
Immunotoxin 4D5scFv-PE40 is a recombinant protein that comprises 4D5scFv antibody as a targeting module and fragment of Pseudomonas exotoxin A as an effector (toxic) one. The immunotoxin has shown pronounced antitumor effect on cancer cells overexpressing HER2 receptor in vitro and on HER2-positive experimental tumors in vivo. We clarified the mechanism of 4D5scFv-PE40 activity that is of particular importance in the case of targeted therapeutic agent aimed at personalizing treatment of disease in relation to molecular genetic characteristics of each patient. After specific binding to HER2 on the cell surface and clathrin-mediated endocytosis the immunotoxin passes through retrograde trafficking route. During this route the immunotoxin molecule is supposed to undergo enzymatic processing that ends in separation of C-terminal and N-terminal fragments of the immunotoxin. Finally, C-terminal functionally active fragment of 4D5scFv-PE40 arrests protein synthesis in cytoplasm followed by cell death via apoptosis.
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