Targeting Toll-Like Receptors
Currently, ARS is treated with supportive measures, but products under development aim at limiting the damage caused by acute radiation syndrome resulting from exposure to a high dose of radiation over a short period of time, usually minutes. Radiation exacts its biggest toll on rapidly dividing cells, with hematopoietic stem cells and progenitor cells of the bone marrow being the most sensitive to radiation damage and nerve cells being the least sensitive.
ARS is categorized into three syndromes, which occur with increasing dose exposure, including hematopoietic or bone marrow syndrome (HP/BM), gastrointestinal syndrome (GI), and central nervous system or cardiovascular syndrome (CNS/CV). Among individuals who have been exposed to moderate to high levels of radiation, many will have received enough radiation to severely damage but not kill their bone marrow cells. While they may recover from initial injuries through supportive care, bone marrow damage will render them susceptible to severe infection for 1–2 months following the exposure.
Countermeasures under development in companies funded under federal programs range from stem cell treatments (e.g., Prochymal) to toll-like receptor agonists (e.g., CBLI’s candidates). CBLI is furthest along with its lead candidate CBLB502.
The company has thus far completed two clinical trials that demonstrated sufficient safety of the drug candidate at doses equivalent to those that produced efficacy in animals. It has also identified biomarkers that, in keeping with the “animal rule,” can act as surrogate efficacy markers in humans. Next steps include repeating the studies under GLP conditions and extending the human clinical trials from the original 150 individuals.
CBLI explains that its protectan compounds rescue mammals from lethal doses of radiation by suppressing apoptotic cell death and stimulating regeneration in critical HP and/or GI cells. The company is currently developing recombinant derivatives of microbial factors that are natural regulators of apoptosis. CBLB502 is a derivative of bacterial flagellin altered to reduce its immunogenicity while retaining its ability to activate a specific signal transduction pathway responsible for tissue protection, Andrei Gudkov, Ph.D., CBLI’s CSO and svp basic science, told GEN.
“Mobilization of natural tissue-protecting mechanisms is initiated by binding of the drug to cellular receptor toll like receptor 5 (TLR5), resulting in activation of the NF-kB pathway downstream,” he explained. “The reason we chose this approach for tissue protection from lethal stresses is because activation of NF-kB leads to blocking apoptosis, defined as the major reason for underlying cause of acute radiation syndrome.
“Apoptosis doesn’t occur in every cell and tissue but more so in two major tissues: hematopoietic tissue and certain parts of the gastrointestinal tract. If we can protect only these two tissues from radiation, exposed individuals could survive significantly higher doses of radiation since other tissues are far more resistant.”
Why bacterial protein? “We were looking for natural factors that would be involved in controlling apoptosis and were thinking about what in nature could have a natural interest in protecting our cells from apoptosis,” Dr. Gudkov noted. “These considerations brought our attention to our own microflora.
“Many components of our intestinal microflora have co-existed with our organism for millions of years and depend on the viability of their environment, which is within the cells of the gut. Our prediction was that our microflora evolved to produce anti-apoptotic factors, which if identified could be used into pharmaceutical agents.”
And, protecting the GI tract after radiation exposure, Dr. Gudkov said, is much more difficult than reconstituting damaged bone marrow. “At least you can do bone marrow transplantation in the marrow but not in the gut.”
Dr. Gudkov said that CBLB502 appears to act as both a radioprotectant and a mitigator of lethal effects; i.e., it can be given at time points after radiation exposure and produce a survival benefit. In nonhuman primates, he said, “you can give this drug to animals irradiated 48 hours prior to the drug and still see significant improvement in survival.”
As biotech companies conducting biodefense projects get more federal dollars, investor interest will increase. For example, some large institutional investors have already acquired stakes in Cleveland BioLabs.
Additionally, analysts and company executives point to another factor that will help boost investor enthusiasm: newer federal programs like BARDA have become more sophisticated in their dealings with the biotech industry. “BARDA understands it has to attract small biotechnology companies and that these companies are not Boeing, with the infrastructure to administer complex DoD contracts,” McManus pointed out. “BARDA has been flexible and helpful in bringing us up to speed.”