Novel medical countermeasure to mitigate potentially lethal acute radiation syndrome

Signablok, Inc. received a $155,857 Project Grant award on September 19, 2025, from the National Institutes of Health (NIH) Office of the Director under the Trans-NIH Research Support program (CFDA 93.310). The award, with a completion date of August 31, 2026, supports the development of a novel medical countermeasure (MCM) to mitigate acute radiation syndrome (ARS). The company is developing GA31, a ligand-independent TREM-1 (Triggering Receptor Expressed on Myeloid Cells-1) inhibitory peptide formulated into macrophage-specific lipopeptide complexes designed for delayed administration (at least 24 hours post-radiation exposure) to extend survival in radiation-exposed patients and casualties.

The proposed therapeutic approach addresses persistent inflammation following acute radiation exposure by targeting macrophage-driven inflammatory responses. Signablok's ligand-independent inhibitor design represents an advancement over previous TREM-1 blockers that have demonstrated clinical setbacks, and the macrophage-targeted delivery mechanism is intended to improve both drug efficacy and half-life. This research aligns with the Trans-NIH Research Support program's focus on innovative, high-impact biomedical research addressing significant public health challenges. The project builds upon Signablok's demonstrated specialization in TREM-1 inhibitor development, as evidenced by their portfolio of prior NIH-funded awards totaling approximately $613,811 across multiple institutes since 2023.

Abstract

Despite significant advances, gaps remain in developing treatments that address persistent inflammation that ensue after acute radiation exposure. The long-term objective of the proposed project is to develop a well-tolerable and effective first-in-class medical countermeasure (MCM) designed for mitigation and treatment of potentially lethal acute radiation syndrome (ARS) and administered at least 24 H post-radiation to significantly extend survival of irradiated patients and radiation casualties. Radiation injury is accompanied by macrophage-driven uncontrolled inflammation. Ionizing radiation increases expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in macrophages. In animals, TREM-1 has been shown to contribute to worse survival after total body irradiation (TBI). This implicates TREM-1 as a promising emerging target to develop a novel MCM for radiation injury. Current TREM-1 blockers are all ligand-dependent and attempt to block binding of TREM-1 to its multiple known and unknown ligands, bearing thus high risk of drug failure in clinical efficacy testing. First clinical TREM-1 blocker LR12 recently failed to reach significance for the primary endpoint in phase IIB sepsis trial. To minimize the risk of failure in the clinic, we developed ligand-independent TREM-1 inhibitory peptide sequence GF9 that can be used as a part of trifunctional peptide GA31 formulated into macrophage- specific lipopeptide complexes (LPC) to improve its half-life and targeting. Macrophage-targeted delivery also addresses the potential for different TREM-1-expressing cell types (e.g., neutrophils VS macrophages) playing different roles in the pathogenesis of inflammatory diseases. TREM-1 blockade by GA31-LPC inhibits uncontrolled inflammatory response and ameliorates the disease in animal models of sepsis, acute respiratory distress syndrome, sulfur mustard-induced lung injury, cancer, arthritis, retinopathy, and other inflammation-associated diseases. GA31-LPC is safe and well-tolerable by healthy and diseased animals. The major goal of the proposed research is to test the hypothesis that therapeutic blockade of TREM-1 by using GA31-LPC will significantly extend survival of mice exposed to LD70/30 radiation dose when administered at 24 H or later post-radiation. Specific aims of this project are to: 1) generate, characterize and test GA31-LPC in vitro; and 2) determine the in vivo feasibility of using GA31-LPC as a therapeutic MCM to significantly extend survival of mice exposed to LD70/30 radiation dose. We will generate GA31-LPC, characterize its composition, size and stability, and test in vitro in cell- based assays. We will next test GA31-LPC in mice exposed to LD70/30 radiation dose for its ability to improve 30 day animal survival when systemically administered 24 or 48 H post-TBI. If successful, this project will generate preliminary data supporting the development of a new mechanism-based, well- tolerable and effective MCM for mitigation and treatment of potentially lethal ARS.