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 bone marrow hematopoiesis is one of the first clinical signs of excessive radiation exposure, often leading to death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a 14 kDa cytokine that stimulates bone marrow cells to divide and differentiate into neutrophils and macrophages. Recombinant human GM-CSF is used to treat chemotherapy- induced neutropenia in cancer patients and accelerate bone marrow recovery following transplantation. Recent studies suggest that hematopoietic factors such as GM-CSF can accelerate white blood cell recovery and improves survival in animal models of ARS. GM-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 GM-CSF analogs that do not require frequent dosing could provide significant treatment advantages in a nuclear emergency scenario, where healthcare worker time will be at a premium and daily dosing of patients may prove difficult. We developed a long-acting human GM-CSF analog using site-specific PEGylation technology. We also developed a murine GM-CSF analog of our lead human GM-CSF analog for testing efficacy of the protein in rodents (human GM-CSF is inactive in rodents). Our long-acting PEG-GM-CSF analog has a longer half-life than GM-CSF in rats and is significantly more effective than GM-CSF at accelerating neutrophil recovery in chemotherapy-treated rats. The primary goal of this Phase I SBIR grant is to demonstrate the feasibility of using this novel, long-acting GM-CSF analog to accelerate white blood cell recovery and improve survival in a mouse model of ARS. The murine PEG GM-CSF protein will be used for these studies. In addition we will optimize processes for manufacture of the human PEG-GM-CSF 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 long-acting GM-CSF analog may provide physicians with a more effective and more convenient therapy for the treatment of the hematopoietic complications of ARS, and improve overall survival in this patient population.
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 GM-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 GM-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|