Abstract
Given an ever-increasing risk of nuclear and radiological emergencies, there is a critical need for development of medical radiation countermeasures (MRCs) that are safe, easily administered, and effective in preventing and/or mitigating the potentially lethal tissue damage caused by acute high-dose radiation exposure. Because the efficacy of MRCs for this indication cannot be ethically tested in humans, development of such drugs is guided by the Food and Drug Administration's Animal Efficacy Rule. According to this rule, human efficacious doses can be projected from experimentally established animal efficacious doses based on the equivalence of the drug's effects on efficacy biomarkers in the respective species. Therefore, identification of efficacy biomarkers is critically important for drug development under the Animal Efficacy Rule. CBLB502 is a truncated derivative of the Salmonella flagellin protein that acts by triggering Toll-like receptor 5 (TLR5) signaling and is currently under development as a MRC. Here, we report identification of two cytokines, granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), as candidate biomarkers of CBLB502's radioprotective/mitigative efficacy. Induction of both G-CSF and IL-6 by CBLB502 1) is strictly TLR5-dependent, 2) occurs in a CBLB502 dose-dependent manner within its efficacious dose range in both nonirradiated and irradiated mammals, including nonhuman primates, and 3) is critically important for the ability of CBLB502 to rescue irradiated animals from death. After evaluation of CBLB502 effects on G-CSF and IL-6 levels in humans, these biomarkers will be useful for accurate prediction of human efficacious CBLB502 doses, a key step in the development of this prospective radiation countermeasure.
Footnotes
This work was supported by the U.S. Department of Defense's Defense Threat Reduction Agency [Grants H.10014_07_AR_R (to V.K.S.), HDTRA1-07-C-0021 (to E.F.), HDTRA1-11-C-0008 (to V.I.K.)]; the U.S. Department of Defense Chemical Biological Medical Systems [Grant W9113M-08-C-0151] (to Cleveland BioLabs, Inc.); the U.S. Department of Health and Human Services Biomedical Advanced Research and Development Authority [Grant HHSO100200800059C] (to A.V.G.); and the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grants R01AI080446, RC2AI087616] (to A.V.G.).
V.I.K., A.N.S., F.B., Y.K., I.S., A.C., R.K.M., A.P., A.V.G., and E.F. are employees or paid consultants of Cleveland Biolabs Inc., a company that has a commercial interest in the results of this research.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- TBI
- total body irradiation
- AFRRI
- Armed Forces Radiobiology Research Institute
- ARS
- acute radiation syndrome
- AUC
- area under the curve
- FDA
- Food and Drug Administration
- G-CSF
- granulocyte colony-stimulating factor
- GM-CSF
- granulocyte-macrophage colony-stimulating factor
- HP
- hematopoietic
- IL
- interleukin
- IP-10
- interferon γ-induced protein 10kDa
- KC
- keratinocyte chemoattractant
- MCP-1
- monocyte chemotactic protein-1
- MIG
- monokine induced by interferon γ
- MIP-2
- macrophage inflammatory protein-2
- MRC
- medical radiation countermeasure
- NF-κB
- nuclear factor-κB
- NHP
- nonhuman primate
- PD
- pharmacodynamic
- PK
- pharmacokinetic
- SCF
- stem cell factor
- TLR
- Toll-like receptor
- TNFα
- tumor necrosis factor α
- TPO
- thrombopoietin.
- Received May 2, 2012.
- Accepted July 26, 2012.
- U.S. Government work not protected by U.S. copyright
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