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 in 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. G- CSF has a short half-life in humans, which necessitates daily dosing, 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 worker time will be at a premium and daily dosing of patients may prove difficult. We developed rationally designed, long-acting G-CSF analogs through site-specific chemical modification of the protein with polyethylene glycol (PEG). Our long-acting PEG-G-CSF analog has a longer half-life than unmodified G-CSF and is significantly more effective than G-CSF at accelerating neutrophil recovery in chemotherapy-treated rats. Our site-specific PEGylated G-CSF analog was more potent than the leading commercial PEGylated G-CSF product in neutropenic rats. The primary goal of this Phase I SBIR grant is to demonstrate the feasibility of using our novel, long-acting G-CSF analog to accelerate neutrophil recovery and improve survival in a mouse model of ARS. In addition we will optimize processes for manufacture of the protein under GLP (Good Laboratory Practices) conditions and measure the safety profile and pharmacokinetic properties of the protein in IND-enabling, GLP animal pharmacology and toxicology studies, which are required by the FDA prior to testing the compound in humans. The improved characteristics of our novel G-CSF analog may provide physicians with a more effective and more convenient therapy for the treatment of the hematopoietic complications of ARS, an improve overall survival in ARS patients compared to existing therapies.
Development of radiological/nuclear medical countermeasures to treat Acute Radiation Syndrome (ARS) is a high priority research area for NIAID. The primary goal of this Phase I SBIR grant is to demonstrate the feasibility of using a novel, long-acting G-CSF analog to improve survival in a mouse model of ARS. In addition we will optimize processes for manufacture of the protein under GLP (Good Laboratory Practices) conditions and perform many of the GLP animal safety and toxicology studies required by the Food and Drug Administration prior to testing the compound in humans. Our long-acting G-CSF analog may prove useful for improving survival in people exposed to an otherwise lethal dose of radiation as a result of a radiological/nuclear disaster.
|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|