SBIR-STTR Award

eNamptorTM: a Humanized mAB to Reduce the Severity of Radiation Pneumonitis and Fibrosis
Award last edited on: 5/20/2023

Sponsored Program
STTR
Awarding Agency
NIH : NHLBI
Total Award Amount
$2,300,001
Award Phase
2
Solicitation Topic Code
838
Principal Investigator
Joe G N Garcia

Company Information

Aqualung Therapeutics Corporation

1790 East River Suite 205
Tucson, AZ 85718

Research Institution

MRI Global

Phase I

Contract Number: 1R42HL152888-01
Start Date: 6/1/2020    Completed: 5/31/2021
Phase I year
2020
Phase I Amount
$300,001
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.

Public Health Relevance Statement:
NARRATIVE Radiation-induced lung injury (RILI) is a serious lung toxicity of ionizing radiation in patients receiving radiotherapy (for a variety of cancers) with radiation-induced pneumonitis and fibrosis both potentially lethal outcomes. Current therapies for RILI are extremely limited with only high dose corticosteroids utilized as a controversial treatment with limited efficacy at best and with serious toxicities. We have identified eNAMPT as a novel therapeutic target for RILI given its capacity to potently induce lung and systemic inflammation and generated, eNamptorTM, the eNAMPT-neutralizing, humanized monoclonal antibody, as a therapeutic strategy for treat RILI by reducing cytokine storm, organ dysfunction and potentially morbidity and lethality of ionizing radiation exposure. This STTR Phase I/II application is designed to evaluate eNamptorTM in RILI.

Project Terms:
Address; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Arizona; Attenuated; base; Biotechnology; Bone Marrow; Cancer Patient; Canis familiaris; Cells; Cessation of life; Characteristics; Chest; Clinic; Clinical; Collaborations; companion diagnostics; Complex; Critical Illness; cytokine; cytokine release syndrome; Data; design; Detection; Development; Dose; Enzymes; Exhibits; Exposure to; extracellular; Fibrosis; Functional disorder; Gases; humanized monoclonal antibodies; Impairment; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Ionizing radiation; irradiation; Ligands; Lung; lung injury; Malignant Neoplasms; Modality; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; mouse model; multidisciplinary; Mus; new therapeutic target; Nicotinamide adenine dinucleotide; nicotinamide phosphoribosyltransferase; novel; novel therapeutics; Nuclear Accidents; Organ; Outcome; Patients; Pattern; pharmacokinetics and pharmacodynamics; Pharmacology and Toxicology; Phase; phase 2 study; polyclonal antibody; pre-clinical; Pre-Clinical Model; precision medicine; preclinical study; Proteins; Pulmonary Fibrosis; Pulmonary Inflammation; Radiation; Radiation exposure; Radiation Fibrosis; Radiation Pneumonitis; Radiation therapy; Radiolabeled; Rattus; Reactive Oxygen Species; Relapse; Risk; Severities; Site; Small Business Technology Transfer Research; Solid; stable cell line; standard of care; Steroids; Therapeutic; therapeutic target; Tissues; TLR4 gene; Toll-like receptors; Toxic effect; Toxicology; Treatment Efficacy; Universities; Vascular Permeabilities; Whole-Body Irradiation

Phase II

Contract Number: 4R42HL152888-02
Start Date: 6/1/2020    Completed: 5/31/2023
Phase II year
2021
(last award dollars: 2022)
Phase II Amount
$2,000,000

The development of radiation-induced lung injury (RILI) is a potentially fatal toxicity in cancer patientsundergoing thoracic radiotherapy or in individuals exposed to ionizing radiation (IR) from a nuclear incident. Thepathobiology of radiation pneumonitis and radiation-induced lung fibrosis (RILF) is complex but includes thedeleterious effects of unchecked inflammation (reactive oxygen species, cytokines, inflammatory cells) thatincrease vascular permeability, impair gas transfer and promote fibrosis. Although Toll-like receptors (TLRs) andcytokines 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. Thestandard 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 effectivetherapeutic 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 dysregulatedinflammatory 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 keycontributor 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 havedeveloped eNamptorTM, an effective eNAMPT-neutralizing humanized mAb that is now in stable cell linedevelopment. This STTR Fast Track Phase I/II application seeks to confirm that eNamptorTM is a noveltherapeutic strategy in preclinical models of WTLI and PBI/BM5 (partial body irradiation, 5% bone marrowsparing). We speculate that eNamptorTM will surpass the protection observed in mice receiving high dosecorticosteroids, thereby addressing a serious unmet need to reduce the risk and severity of RILI following IRexposure. Aqualung Therapeutics (ALT), an early stage biotechnology start-up, in collaboration with itsacademic partner (Univ. of Arizona) has assembled a highly skilled multidisciplinary team to evaluateeNamptorTM as a therapeutic strategy in preclinical murine models of WTLI (SA #1) and PBI/BM5 (SA #2). Wewill also assess the utility of a radiolabeled-NAMPT mAb probe, ProNAmptorTM, as a companion diagnosticstrategy that defines organ-specific sites of IR-induced NAMPT expression. STTR Phase II studies will profilethe pharmacodynamic (PD) and pharmacokinetic (PK) (SA #4) and toxicological characteristics of eNamptorTMmAb (SA #5). The proof of concept of eNamptorTM’s utility in RILI will lead to a successful FDA IND application.

Public Health Relevance Statement:
NARRATIVE Radiation-induced lung injury (RILI) is a serious lung toxicity of ionizing radiation in patients receiving radiotherapy (for a variety of cancers) with radiation-induced pneumonitis and fibrosis both potentially lethal outcomes. Current therapies for RILI are extremely limited with only high dose corticosteroids utilized as a controversial treatment with limited efficacy at best and with serious toxicities. We have identified eNAMPT as a novel therapeutic target for RILI given its capacity to potently induce lung and systemic inflammation and generated, eNamptorTM, the eNAMPT-neutralizing, humanized monoclonal antibody, as a therapeutic strategy for treat RILI by reducing cytokine storm, organ dysfunction and potentially morbidity and lethality of ionizing radiation exposure. This STTR Phase I/II application is designed to evaluate eNamptorTM in RILI.

Project Terms: