Development of radiological/nuclear medical countermeasures to treat Acute Radiation Syndrome (ARS) is a high priority research area for NIAID. Bone marrow is one of the most sensitive tissues to radiation damage and impaired hematopoiesis is one of the first clinical signs of excessive radiation exposure, often resulting i death. Granulocyte colony-stimulating factor (G- CSF) is a 19 kDa protein that stimulates bone marrow cells to divide and differentiate into neutrophils. Recombinant human G-CSF is widely used to treat chemotherapy-related neutropenia in cancer patients, and recent studies indicate that it improves overall survival in animal models of ARS, although the drug requires daily administration, which may not be possible following a radiological/nuclear disaster. G-CSF has a short half-life in humans, which necessitates daily dosing for two weeks or more, and may not optimize therapeutic benefits of the protein for patients. Long-acting G-CSF analogs that do not require frequent dosing could provide significant treatment advantages in a nuclear emergency setting, where healthcare provider time will be at a premium and daily dosing of patients may not be possible. We developed a rationally designed, long-acting G-CSF analog through site-specific chemical modification of the protein with polyethylene glycol (PEG). Our long-acting PEG-G-CSF analog has a 10-fold half-life than unmodified G-CSF and is significantly more effective than G-CSF at accelerating neutrophil recovery in chemotherapy-treated rats. Studies performed during the Phase I SBIR grant demonstrated the utility of this novel, long-acting G-CSF analog for improving survival in a well characterized mouse ARS model. In contrast to G-CSF, our long-acting G-CSF analog required only a single administration to be effective. Notably, 100% (20/20 mice) of lethally irradiated mice treated 24h post-irradiation with a single administration of this long-acting G-CSF analog survived 30 days compared to a mortality rate of 50 % (10/20 mice) for vehicle-treated mice. Our long-acting G-CSF analog also improved survival compared to placebo following multiple injections into irradiated mice. Irradiated mice treated with our long-acting G-CSF analog showed accelerated recovery of neutrophils, red blood cells and platelets compared to vehicle-treated mice, indicating that the protein positively affected recovery of multiple blood cell types. The Phase II grant has three major goals. First, we will perform additional studies in irradiated mice to determine how long after irradiation the drug can be administered and still improve survival. Second, we will determine whether the protein improves survival of lethally-irradiated non-human primates, which is the gold standard ARS model adopted by the FDA. Third, we will measure the safety profile and pharmacokinetic properties of the protein in IND-enabling, GLP animal pharmacology and toxicology studies in order to identify safe doses of the drug for testing in humans. Our novel G- CSF analog will provide physicians with an effective and convenient therapy for the treatment of all of the major hematopoietic complications of ARS, and improve survival of subjects exposed to high radiation doses as a result of a radiological/nuclear disaster. The fact that the drug requires only a single administration for effectiveness represents a significance advance in the treatment of ARS and will optimize healthcare provider time in a radiological/nuclear emergency setting, where patient numbers are expected to overwhelm available healthcare resources. The drug should prove useful for treating other diseases for which G-CSF is used as a therapy, such as neutropenia resulting from chemotherapy use in cancer patients.
Development of radiological/nuclear medical countermeasures to treat Acute Radiation Syndrome (ARS) is a high priority research area for NIAID. The Phase I SBIR studies showed that our long- acting G-CSF analog significantly improved survival of lethally irradiated mice compared to a placebo. Unlike G-CSF, which is administered daily for 10-20 days following radiation exposure, our long-acting G-CSF analog was effective when administered only once. Improved survival of irradiated mice treated with our long-acting G-CSF analog correlated with accelerated recovery of multiple blood cell types, including neutrophils, red blood cells and platelets, which is a novel finding. The primary goals of this Phase II SBIR grant are (1) to demonstrate the feasibility of using this novel, long-acting G-CSF analog to improve survival in a non-human primate ARS model;(2) determine how long after radiation exposure the drug can be administered and still provide a survival benefit;and (3) complete IND-enabling animal toxicology studies required by the FDA to begin testing the protein in human safety studies and pivotal animal ARS studies. Our long- acting G-CSF analog will prove useful for improving survival of humans exposed to an otherwise lethal dose of radiation as a result of a radiological/nuclear disaster. The long half-life of the drug will allow patients to be treated only once with the drug, which will optimize healthcare provider time in a radiological/nuclear emergency setting. The drug should prove useful for treating other diseases for which G-CSF is used as a therapy, such as neutropenia resulting from chemotherapy use in cancer patients.
|Plett, Paul Artur; Chua, Hui Lin; Sampson, Carol H et al. (2014) PEGylated G-CSF (BBT-015), GM-CSF (BBT-007), and IL-11 (BBT-059) analogs enhance survival and hematopoietic cell recovery in a mouse model of the hematopoietic syndrome of the acute radiation syndrome. Health Phys 106:7-20|