Phase I Amount
$2,844,359
The severity of radiation injury in humans is largely determined by high sensitivity of the gastrointestinal (GI) tract, yet no drugs are approved for this indication. This proposal is focused on a novel clinical-stage drug candidate, Protectan CBLB502, a toll-like receptor 5 (TLR5) agonist capable of effective mitigation of otherwise lethal radiation-induced GI injury in mice and non-human primates (NHPs). A comprehensive understanding of mechanisms of action is required for drug development under the FDA Animal Efficacy Rule. Accordingly, the main objective of this proposal is to use mouse and NHP models to characterize in detail the mitigating effect of CBLB502 on various elements of the GI system and to identify cellular and molecular mediators of this effect. Specifically, our multi-institutional collaborative team will: (i) create a comprehensive "histological atlas" illustrating the mitigating effects of CBLB502 on various elements of GI infrastructure damaged by radiation, (ii) define the target organs that contribute to the GI radiomitigation activity of CBLB502 with specific focus on bone marrow and liver, and (iii) identify primary and secondary cellular and molecular responders to CBLB502 with the expectation of defining molecular conductors of the radiomitigating function of the drug as well as novel efficacy biomarkers. Completion of this program should create a solid mechanistic base for translation of animal data into a well-justified projected human efficacious dose and will be critical for FDA approval of CBLB502 as a medical countermeasure to mitigate GI radiation damage.
Public Health Relevance Statement: Protectan CBLB502, is a clinical stage drug candidate effective against multiple components of Acute Radiation Syndrome including GI injury. Completion of the proposed program will facilitate development and FDA approval of CBLB502 by providing critical insights in the mechanisms of its activity.
NIH Spending Category: Biodefense; Biotechnology; Digestive Diseases; Emerging Infectious Diseases; Infectious Diseases
Project Terms: Acute; Address; Agonist; Ailmentary System; Alimentary Canal; Alimentary System; alimentary tract; animal data; animal efficacy; animal tissue; Animals; Area; Atlases; autocrine; Autocrine Systems; base; bioengineering; bioengineering/biomedical engineering; biological signal transduction; biomarker; Biomedical Engineering; Bleeding; blood loss; body system, hepatic; Body Tissues; Bone Marrow; Cell Communication and Signaling; Cell Signaling; Cells; Cessation of life; chemoattractant cytokine; chemokine; Clinical; cytokine; Cytokines, Chemotactic; Death; Development; digestive canal; Digestive System; Digestive System (All Sites); Digestive Tract; Dose; drug candidate; drug development; drug mechanism; drug/agent; Drugs; Elements; Engraftment; expectation; Exposure to; Flagellin; Funding; gastrointestinal; Gastrointestinal Body System; Gastrointestinal Injury; gastrointestinal system; Gastrointestinal Tract; Gastrointestinal tract structure; Gastrointestinal Tract, Small Intestine; Gene Expression Monitoring; Gene Expression Pattern Analysis; Gene Expression Profiling; gene product; Gene Targeting; Genetics, in situ Hybridization; GI Tract; Hand; Hematologic Body System; Hematopoietic; Hematopoietic Body System; Hematopoietic System; Hemorrhage; Hepatic Cells; Hepatic Parenchymal Cell; Hepatocyte; Histological Technics; Histological Techniques; Homologous Chemotactic Cytokines; Hour; Human; Human, General; improved; In Situ; In Situ Hybridization; in situ Hybridization Staining Method; Infrastructure; injured; insight; Intercrines; Intestines, Small; Intracellular Communication and Signaling; intramuscular administration of drug; Intramuscular Injections; Investigators; irradiation; language translation; Ligands; Liver; Liver Cells; Macaca mulatta; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Medical; Medical center; Medication; Mice; Mission; Modeling; Molecular; Mother Cells; Murine; Mus; National Institute of Allergy and Infectious Disease; National Institutes of Health; National Institutes of Health (U.S.); new approaches; NIAID; NIH; non-human primate; nonhuman primate; novel; novel approaches; novel strategies; novel strategy; Organ; Organ System, Gastrointestinal; Organ System, Hematologic; organ system, hepatic; paracrine; Pathology; pathway; Pathway interactions; Pharmaceutic Preparations; Pharmaceutical Preparations; Play; Profilings, Gene Expression; Progenitor Cells; programs; Programs (PT); Programs [Publication Type]; Protective Agents; Protective Drugs; Proteins; Radiation; Radiation Injuries; Radiation Syndromes; Radiation, Whole-Body; Radio; ray (radiation); Recovery; Refrigeration; release factor; Reporter; Research Infrastructure; Research Personnel; Research Resources; Researchers; Resources; response; Reticuloendothelial System, Bone Marrow; Rhesus; Rhesus Macaque; Rhesus Monkey; Role; Severities; Signal Transduction; Signal Transduction Pathway; Signal Transduction Systems; Signaling; SIS cytokines; Site; small bowel; Small Intestines; social role; Solid; Source; Staging; stem; Stem cells; Targetings, Gene; Technics, Histologic; Techniques, Histologic; Technology; Testing; Thrombocytopenia; Thrombopenia; TIL3; Time; Tissues; TLR5; TLR5 receptor; toll-5 receptor; Toll-Like Receptor 5; Toll/Interleukin-1 Receptor-Like Protein 3; Total Body Irradiation; Transcript Expression Analyses; Transcript Expression Analysis; transcription factor; Translating; Translatings; Translations; United States National Institutes of Health; Whole-Body Irradiation; Work
