Research Project
10274779
ABSTRACT The development of radiation-induced lung injury (RILI) is a potentially fatal toxicity in cancer patients undergoing thoracic radiotherapy or in individuals exposed to ionizing radiation (IR) from a nuclear incident. The pathobiology of radiation pneumonitis and radiation-induced lung fibrosis (RILF) is complex but includes the deleterious effects of unchecked inflammation (reactive oxygen species, cytokines, inflammatory cells) that increase vascular permeability, impair gas transfer and promote fibrosis. Although Toll-like receptors (TLRs) and cytokines are potential therapeutic targets for reducing RILI, experimental and clinical strategies to neutralize IR- induced proinflammatory cytokine effects or to block inflammatory cell infiltration have been disappointing. The standard of care, high dose corticosteroids, remains controversial due to long term complications and frequent, potentially fatal relapses. Thus, there is an unmet need to identify novel RILI therapeutic targets and effective therapeutic anti-inflammatory strategies. Our preclinical studies utilizing whole lung thoracic irradiation (WTLI), identified a cytozyme, nicotinamide phosphoribosyltransferase (NAMPT), as a novel RILI therapeutic target. NAMPT exists as both an intracellular enzyme (iNAMPT) catalyzing nicotinamide adenine dinucleotide (NAD) synthesis and as an extracellular inflammatory cytokine (eNAMPT). We have shown that eNAMPT is a damage- associated molecular pattern protein (DAMP) and a ligand for TLR4 to potently induce the dysregulated inflammatory response that results in cytokine storm, organ dysfunction, and death in severe critical illnesses. We have also shown that NAMPT expression and secretion is markedly increased by radiation and is a key contributor to RILI development and severity as NAMPT heterozygous mice exhibit reduced WTLI-induced RILI. Furthermore, a polyclonal eNAMPT pAb effectively reduces WTLI-induced pneumonitis and fibrosis. We have developed eNamptorTM, an effective eNAMPT-neutralizing humanized mAb that is now in stable cell line development. This STTR Fast Track Phase I/II application seeks to confirm that eNamptorTM is a novel therapeutic strategy in preclinical models of WTLI and PBI/BM5 (partial body irradiation, 5% bone marrow sparing). We speculate that eNamptorTM will surpass the protection observed in mice receiving high dose corticosteroids, thereby addressing a serious unmet need to reduce the risk and severity of RILI following IR exposure. Aqualung Therapeutics (ALT), an early stage biotechnology start-up, in collaboration with its academic partner (Univ. of Arizona) has assembled a highly skilled multidisciplinary team to evaluate eNamptorTM as a therapeutic strategy in preclinical murine models of WTLI (SA #1) and PBI/BM5 (SA #2). We will also assess the utility of a radiolabeled-NAMPT mAb probe, ProNAmptorTM, as a companion diagnostic strategy that defines organ-specific sites of IR-induced NAMPT expression. STTR Phase II studies will profile the pharmacodynamic (PD) and pharmacokinetic (PK) (SA #4) and toxicological characteristics of eNamptorTM mAb (SA #5). The proof of concept of eNamptorTM?s utility in RILI will lead to a successful FDA IND application.
