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. Interleukin-11 (IL-11) is a 19 kDa, non-glycosylated protein that stimulates bone marrow cells to divide and differentiate into platelets. IL-11 exerts effects on a variety of additional tissues, including intestinal cells, where it acts as a survival factor. Recombinant human IL-11 is the only drug currently approved by the FDA to treat chemotherapy- related thrombocytopenia in cancer patients. Recent studies indicate that IL-11 can mitigate some of the hematopoietic and gastrointestinal complications of radiation exposure, and improve overall survival in animal models of ARS. IL-11 has a short half-life in humans, which necessitates daily dosing, and may not optimize therapeutic benefits of the protein for patients. Long-acting IL-11 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 IL-11 analogs through site-specific chemical modification of the protein with polyethylene glycol (PEG). Our long-acting IL-11 analog has a longer half-life than unmodified IL-11 and is significantly more potent than IL-11 at stimulating platelet formation in rats. The primary goal of this Phase I SBIR grant is to demonstrate the feasibility of using our novel, long-acting IL-11 analog to accelerate platelet 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 IL-11 analog may provide physicians with a more effective and more convenient therapy for the treatment of the hematopoietic and gastrointestinal complications of ARS, and 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 IL-11 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 IL-11 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.
Thesaurus Terms: Acute; Adipogenesis Inhibitory Factor; Adopted; Amines; Anemia; Animal Model; Animal Models And Related Studies; Animals; Applications Grants; Area; Assay; Bioassay; Biologic Assays; Biological Assay; Bizzozero's Corpuscle/Cell; Blood Cells; Blood Neutrophil; Blood Platelets; Blood Polymorphonuclear Neutrophil; Blood Segmented Neutrophil; Blood Leukocyte; Blood Megakaryocyte; Body Tissues; Bone Marrow; Bone Marrow Blood-Deriving Cell; Bone Marrow Blood-Forming Cell; Bone Marrow Cells; Bone Marrow Failure; 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 2 Alpha; Common Rat Strains; Dna; Data; Death; Deetjeen's Body; Deoxyribonucleic Acid; 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Interleukin-11; Interleukin-3; Intestinal; Intestines; 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 Leukocyte; Marrow Platelet; Mast-Cell Colony-Stimulating Factor; Mast-Cell Growth Factor; Measures; Medical; Medication; Megakaryocytes; Megalokaryocyte; 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; Neutropenia; Neutrophilic Granulocyte; Neutrophilic Leukocyte; Nuclear; Oprelvekin; Oprelvekin (Interleukin 11); Organ; P-Csf; P-Cell Stimulating Factor; Peg; Pancytopenia; Patients; Pb Element; Peripheral Blood Cell; Persons; Pharmaceutic Preparations; 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Medical Personnel; Meetings; Model Organism; Mouse Model; Neutrophil; Non-Human Primate; Nonhuman Primate; Novel; Pre-Clinical; Preclinical; Public Health Relevance; Radiation Effect; Ray (Radiation); Response; Rhil-11; Thrombocyte/Platelet; Treatment Provider; White Blood Cell; White Blood Corpuscle
