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.
Public Health Relevance: 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.
Public Health Relevance Statement: Cox, George Norbert Narrative 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.
Project Terms: Acute; Adopted; Amgen brand of pegfilgrastim; Amines; Anemia; Animal Model; Animal Models and Related Studies; Animals; Applications Grants; Area; Assay; Bioassay; Biologic Assays; Biological Assay; Blood Cells; Blood Neutrophil; Blood Polymorphonuclear Neutrophil; Blood Segmented Neutrophil; Blood granulocytic cell; Blood leukocyte; Body Tissues; Bone Marrow; Bone Marrow Blood-Deriving Cell; Bone Marrow Blood-Forming Cell; Bone Marrow Cells; Bone Marrow Transplant; Bone Marrow Transplantation; Bone marrow failure; CSF-G/G-CSF (Recombinant Human); Cancer Patient; Canine Species; Canis familiaris; Cell Growth in Number; Cell Multiplication; Cell Proliferation; Cells; Cellular Proliferation; Cessation of life; Characteristics; Chemicals; Chromatography, High Performance Liquid; Chromatography, High Pressure Liquid; Chromatography, High Speed Liquid; Clinical; Clinical Trials; Clinical Trials, Unspecified; Colony Stimulating Factor 3; Colony-Stimulating Factor 2 Alpha; Common Rat Strains; DNA; Data; Death; Deoxyribonucleic Acid; Development; Disasters; Dogs; Dose; Drug Formulations; Drug Kinetics; E coli; ELISA; Effectiveness; Effects of radiation; Emergencies; Emergency Situation; Endotoxins; Enzyme-Linked Immunosorbent Assay; Eosinophil-Mast Cell Growth-Factor; Erythrocyte Burst-Promoting Factor; Escherichia coli; FDA; Feedback; Filgrastim; Filgrastim SD-01; Food and Drug Administration; Food and Drug Administration (U.S.); Formulation; Formulations, Drug; G-CSF (Amgen); G-CSF Recombinant, Human Methionyl; Goals; Government; Grafting, Bone Marrow; Grant; Grant Proposals; Grants, Applications; Granular Leukocytes; Granulocyte Colony-Stimulating Factor; Granulocytic cell; Guidelines; HPLC; Half-Life; Half-Lifes; Health Care Providers; Health Personnel; Healthcare Providers; Healthcare worker; Hematopoiesis; Hematopoietic; Hematopoietic Cellular Control Mechanisms; Hematopoietic Cytokine; Heterogeneity; Heterophil Granulocyte; High Pressure Liquid Chromatography; Human; Human, General; IL-3; IL-3(H); IL3 Protein; In Vitro; Injection of therapeutic agent; Injections; Interleukin 3 (Colony-Stimulating Factor, Multiple); Interleukin 3 Precursor; Interleukin-3; Investigational New Drug Application; Lead; Leukocytes; Liquid substance; Lymphocytopenia; Lymphopenia; MCGF; MULTI-CSF; Macrogols; Mammals, Dogs; Mammals, Mice; Mammals, Rats; Mammals, Rodents; Man (Taxonomy); Man, Modern; Marrow Neutrophil; Marrow Transplantation; Marrow leukocyte; Mast-Cell Colony-Stimulating Factor; Mast-Cell Growth Factor; Measures; Medical; Mice; Modeling; Molecular Configuration; Molecular Conformation; Molecular Stereochemistry; Morbidity; Morbidity - disease rate; Mother Cells; Multilineage-Colony-Stimulating Factor; Multipotential Colony-Stimulating Factor; Murine; Mus; NIAID; National Institute of Allergy and Infectious Disease; Neulasta; Neupogen; Neutropenia; Neutrophilic Granulocyte; Neutrophilic Leukocyte; Nuclear; Organ; P-CSF; P-Cell Stimulating Factor; PEG; PEG SD-01; PEG-rmetHuG-CSF; Pancytopenia; Patients; Pb element; Pegfilgrastim; Pegfilgrastim (Neulasta); Peripheral Blood Cell; Persons; Pharmacodynamics; Pharmacokinetics; Pharmacology and Toxicology; Phase; Physicians; Pluripoietin; Polyethylene Glycols; Polyethylene Oxide; Polyethyleneoxide; Polymorph; Polymorphonuclear Cell; Polymorphonuclear Leukocytes; Polymorphonuclear Neutrophils; Polyoxyethylenes; Post-Translational Modifications; Post-Translational Protein Processing; Posttranslational Modifications; Procedures; Process; Production; Progenitor Cells; Property; Property, LOINC Axis 2; Protein Modification; Protein Modification, Post-Translational; Protein Processing, Post-Translational; Protein Processing, Posttranslational; Protein/Amino Acid Biochemistry, Post-Translational Modification; Proteins; Protocol; Protocols documentation; Protocols, Treatment; RGM; Radiation; Radiation Syndromes; Rat; Rattus; Recombinant G-CSF; Recombinant Granulocyte Colony Stimulating Factor; Recombinant-Methionyl Human Granulocyte Colony-Stimulating Factor; Recombinants; Recovery; Regimen; Relative; Relative (related person); Research Priority; Reticuloendothelial System, Bone Marrow; Reticuloendothelial System, Leukocytes; Rodent; Rodentia; Rodentias; SBIR; SBIRS (R43/44); SCHED; SD-01; SD-01 sustained duration G-CSF; SD-01, polyethylene glycol-conjugated filgrastim; Safety; Schedule; Site; Small Business Innovation Research; Small Business Innovation Research Grant; Solutions; Staging; Stem cells; Subcutaneous Injections; Technology; Testing; Therapeutic; Thrombocytopenia; Thrombopenia; Time; Tissues; Toxicology; Treatment Protocols; Treatment Regimen; Treatment Schedule; USFDA; United States Food and Drug Administration; White Blood Cells; White Cell; analog; analytical method; animal efficacy; animal rule; base; canine; cell type; chemotherapy; clinical investigation; comparative efficacy; conformation; conformational state; design; designing; domestic dog; effect, adverse, radiation; efficacy trial; filgrastrim; flasks; fluid; gene product; good laboratory practice; granulocyte; granulocyte colony stimulating factor; health care personnel; health care worker; health provider; healthcare personnel; heavy metal Pb; heavy metal lead; hematopoietic growth factor; improved; in vivo; liquid; manufacturing process; medical personnel; meetings; model organism; mouse model; neutrophil; non-human primate; nonhuman primate; novel; pre-clinical; preclinical; public health relevance; r-metHuG-CSF; radiation effect; ray (radiation); treatment provider; white blood cell; white blood corpuscle
