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Science 320 (5873): 226-230

Copyright © 2008 by the American Association for the Advancement of Science

An Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models

Lyudmila G. Burdelya,1* Vadim I. Krivokrysenko,2* Thomas C. Tallant,3 Evguenia Strom,2 Anatoly S. Gleiberman,2 Damodar Gupta,1 Oleg V. Kurnasov,4 Farrel L. Fort,2 Andrei L. Osterman,4 Joseph A. DiDonato,3 Elena Feinstein,2{dagger} Andrei V. Gudkov1,2{dagger}

Abstract: The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor–{kappa}B signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.

1 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
2 Cleveland BioLabs, Inc. (CBLI), Buffalo, NY14203, USA.
3 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
4 Burnham Institute for Medical Research, La Jolla, CA 92037, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: andrei.gudkov{at}roswellpark.org; efeinstein{at}cbiolabs.com


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