Protecting Military Personnel, First Responders, and Civilians from the Acute Lethal Doses of Radiation


From the US and global perspectives, biomedical research concerning medical countermeasure development is quite robust, largely due to increased government funding following the 9/11 incident and subsequent rise of terrorist-associated threats. A wide spectrum of radiation countermeasures for specific types of radiation injuries are currently under investigation. However, only a few radiation countermeasures have been fully approved by regulatory agencies for human use during radiological/nuclear contingencies. Additional research effort, with additional funding, will clearly be needed in order to fill this significant, unmet medical health problem.


Radiation countermeasures for emergency use in acute radiation syndrome (ARS) are being developed using small and large animal models following the US Food and Drug Administration (FDA) Animal Rule (because it is unethical to investigate the efficacy of such agents in humans). In collaboration with numerous academic institutions and corporate partners, we are working on developing several radiation countermeasures for the various sub-syndromes of ARS which are under the advanced stages of development. An additional collaborative effort of our team is the identification of appropriate biomarkers for radiation injury. We are currently using several approaches to identify and validate biomarkers for determining dose conversion from animal to human and for confirmation of efficacy. Numerous radiation countermeasures under advanced development are being investigated for efficacy, mechanism of action, and biomarker identification: gamma-tocotrienol (GT3, a component of Vitamin E), BIO 300 (genistein), Ex-RAD (a chlorobenzylsulphone derivative), TLR ligands (CBLB502 - Entolimod, CBLB612, CBLB613), myeloid progenitors, and anti-ceramide antibody.

GT3 is being developed as a radiation countermeasure in collaboration with Prof. Martin Hauer-Jensen of the University of Arkansas Medical Center, Little Rock, AR. It has shown great promise in rodent models and has demonstrated capablility to mobilize progenitors. GT3’s radioprotective efficacy is mediated through G-CSF in the murine model. Recently, it has been found that a single administration of GT3, without additional support (fluids, antibiotics, blood products, etc.), was just as effective as multiple administrations of G-CSF (with full supportive care), the current gold standard of radiation countermeasures approved by the US FDA. Based on the promising results of the pilot study, an in-depth study is being carried out to advance this agent for the FDA approval following Animal Rule. Its biomarkers are being investigated using multiple omics approaches.

Additionally, an anti-ceramide antibody is being developed in collaboration with Prof. Richard Kolesnick of the Memorial Sloan Kettering Cancer Center and Ceramedix, as a radiation countermeasure for gastrointestinal sub-syndrome (GI-ARS). Studies have indicated that this potential countermeasure inhibits ceramide-mediated endothelial apoptosis, which provides significant protection against radiation induced, potentially fatal GI-ARS. Additional studies have shown that a single chain variable fragment (scFv) of the full length antibody molecule is effective in doses one tenth of the full length version.

Other countermeasures being investigated by this team are CBLB612, CBLB613, and myeloid progenitors in collaboration with various academic and corporate partners with support from several funding agencies such as BARDA, NIAID, JPC7, CDMRP, and DMRDP.

Several research projects have been funded by various US government agencies of DoD (DMRDP, DTRA, CDMRP, JPC7) and HHS (NIAID, BARDA).


Drug Discovery

There are two major, but quite different approaches to advance drug discovery. The first being the target-based drug discovery (TBDD) approach that is commonly referred to as the molecular approach. The second approach is the phenotype-based drug discovery (PBDD), also known as physiology-based drug discovery or empirical approach. The majority of the countermeasures currently being developed for ARS employ the PBDD approach, while the TBDD approach is clearly under-utilized.

There is a preference for a ‘hybrid’ strategy which is more reliant on TBDD for the initial drug discovery via large-scale screening of potential candidate agents, while utilizing PBDD for secondary screening of those candidates, followed by tertiary analytics phase in order to pinpoint efficacious candidates that target the specific sub-syndromes of ARS.

Radiation countermeasures for ARS

Only three radiation countermeasures have been fully approved by the US FDA for the mitigation of acute radiation injuries. All three agents are radiomitigators for hematopoietic ARS (H-ARS) and have been extensively studied for efficacy and safety, gaining approval from regulatory authority for use in humans following the Animal Rule. To date, no radioprotector has been approved by the US FDA specifically for either H-ARS or GI-ARS. Similarly, no agent has been approved for GI-ARS, neither protector nor mitigator. Several agents are under investigation.


Numerous biomarkers have been validated/qualified by the US FDA for indications not related to radiation injury. To date, there are no FDA qualified biomarkers for radiation injury. The process of determining biomarkers for radiation injury through the US FDA Animal Rule is quite slow and technically challenging. We are making use of the advances within newer areas of biologic analytics, namely omics; genomics, proteomics, metabolomics and transcriptomics in addition to conventional techniques to identify biomarkers for radiation injury and countermeasure efficacy.


Several promising radiation countermeasures, such as Entolomod (CBLB5020), Myelod progenitors (CLT-008), EX-RAD (ON01210), BIO 300 (genistein), and 5-androstenediol have been investigated using various experimental models for advanced development. These agents have US FDA investigational new drug (IND) status and currently being investigated in clinic for achieving US FDA new drug/biologic application. Biomarkers for some of these countermeasures have been identified.


Significant achievement has been made with several radiation countermeasures for the approval from the US FDA under the Animal Rule. The mechanism of action and biomarkers for few of these agents have been thoroughly investigated.


"Although the search for radiation countermeasures for acute radiation syndrome was initiated more than half a century ago, it remains a largely unmet medical need. Serious effort is being made to have multiple countermeasures for each sub-syndrome of ARS."