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

doi:10.1126/science.1154986

Account Information

Guest Alerts | Access Rights | My Account | Sign In

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 Andrei V. Gudkov¹^,2

Abstract: The toxicity of ionizing radiation is associated with massiveapoptosis in radiosensitive organs. Here, we investigate whethera drug that activates a signaling mechanism used by tumor cellsto suppress apoptosis can protect healthy cells from the harmfuleffects of radiation. We studied CBLB502, a polypeptide drugderived from Salmonella flagellin that binds to Toll-like receptor5 (TLR5) and activates nuclear factor– ${kappa}$ B signaling. A singleinjection of CBLB502 before lethal total-body irradiation protectedmice from both gastrointestinal and hematopoietic acute radiationsyndromes and resulted in improved survival. CBLB502 injectedafter irradiation also enhanced survival, but at lower radiationdoses. It is noteworthy that the drug did not decrease tumorradiosensitivity in mouse models. CBLB502 also showed radioprotectiveactivity in lethally irradiated rhesus monkeys. Thus, TLR5 agonistscould potentially improve the therapeutic index of cancer radiotherapyand 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.

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

The editors suggest the following Related Resources on Science sites:

In Science Signaling

EDITORS' CHOICE
Medicine
Radioprotection: Taking the Toll Road: Paula A. Kiberstis (15 April 2008)
Sci. Signal. 1 (15), ec135. [DOI: 10.1126/stke.115ec135]
| Abstract »

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:

Signalling loops and linear pathways: NF-{kappa}B activation in response to genotoxic stress.: K. Brzoska and I. Szumiel (2008)
Mutagenesis
| Abstract » | Full Text » | PDF »