Problem. No FDA-approved prophylactic Medical Counter Measures (MCMs) are currently available for Ionizing Radiation (IR) exposures that result in Acute Radiation Syndrome (ARS), suggesting an unmet need for such agents. Objective. This is a proposal to develop a safe, well-tolerable and effective agent designed to prevent acute or late radiation effects and prolong survival. The main objective of the Phase I work is to demonstrate feasibility of the proposed approach. Background. Survivability of radiation casualties is determined by progression of ARS to multiple organ dysfunction syndrome, resulting in multiple organ failure all being linked to radiation-induced systemic inflammatory response. Target. Macrophages are key immune cells in the inflammatory processes and play an important role in radiation injury. Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), an inflammation amplifying receptor expressed on macrophages, mediates release of pro-inflammatory cytokines and is critically involved in acute and chronic inflammation-associated diseases. This implicates TREM-1 as a new promising target in inflammation. Agent. First-in-class TREM-1 inhibitory peptide GF9 employs a new, ligand-independent mechanism of action, which is important due to uncertainty of TREM-1 ligand(s). Other TREM-1 blockers (LR12 peptide by Inotrem, France; anti-TREM-1 antibody by Novo Nordisk, Denmark; etc) all attempt to block binding of currently unknown ligands of TREM-1 and have a risk of failure in clinics, while GF9 is an advantageously ligand-independent. Safety of TREM-1 Blockade. TREM-1 inhibitor LR12 is currently in sepsis Phase II trial. While not being able to prove the efficacy of LR12 yet, this trial demonstrated safety of TREM-1 blockade not only in healthy volunteers but also in vulnerable septic patients. Hypothesis. TREM-1 blockade using TREM-1 inhibitory peptide GF9 will prevent the effects of ARS and extend survival. Aims. To test that TREM-1 blockade protects against radiation effects and improves survival, we will: 1) generate and test GF9 sequence-based injectables in vitro, and 2) determine the in vivo feasibility of using GF9 to prevent the effects of ARS and extend survival. Supporting Data. GF9 is well tolerable in healthy and diseased mice up to at least 300 mg/kg with a therapeutic dose range of 5-25 mg/kg. In animals, GF9 suppresses systemic inflammatory response, lowers serum/tissue CSF-1, TNFa, IL-1b, IL-6 and fibrinogenesis markers and ameliorates sepsis, arthritis, retinopathy, liver disease, and cancer. This strongly suggests that GF9 will be effective in preventing the effects of ARS in vivo and will reach the milestone of efficacy at the LD70/30 or greater radiation dose levels.
