Evaluation of the Therapeutic Potential of eNAMPT Monoclonal Antibodies (mAbs) in Preclinical Models of Acute Lung Injury and ARDS
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Author
Sammani, SaadIssue Date
2019Keywords
ARDSAdvisor
Garcia, Joe G.N.
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The University of Arizona.Rights
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.Embargo
Thesis not available (per author's request)Abstract
Acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung disease which results in acute respiratory failure. ARDS affects more than 400,000 individuals annually in the USA with high mortality rate (30–40%). Mechanical ventilation (MV) is an essential part of the current ARDS management. However, MV itself may lead to ARDS. There remains a serious unmet need for effective therapies for ARDS. Our previous lab results demonstrated that excessive mechanical stress induces spatially-localized nicotinamide phosphoribosyl-transferase (NAMPT) expression (1) with robust expression and secretion by lung endothelial cells (ECs) into the circulation with extracellular NAMPT (eNAMPT) a novel biomarker in ARDS (1, 2). We have used a polyclonal NAMPT antibody as a potential therapy in many preclinical ARDS animal models such as ventilator-induced Lung Injury (VILI) (3), LPS-induced inflammatory lung injury (4), pulmonary artery hypertension (PAH) (5), and radiation-induced lung injury (RILI) (12). Since the polyclonal antibodies cannot be used in humans, we next developed a mouse mAb that can neutralize eNAMPT in humans. From 2 murine eNAMPT mAbs, 2 were selected and 50 humanized mAbs generated. These were screened in vitro for eNAMPT neutralization and 7 humanized mAbs selected for evaluation in C57/BL6 mice (8–12 wks.) utilizing our preclinical LPS and two-hit (LPS+VILI) ALI models. We further designed an integrated ALI severity scoring system to evaluate responses these Abs. This scoring system is composed of four elements: total bronchoalveolar lavage (BAL) cell counts (CC), total BAL protein levels, lung tissue cell infiltration and alveolar wall thickness. Of the seven eNAMPT mAbs, UU, XX and P were the most effective in attenuating lung injury in our preclinical ARDS models. As a conclusion, application of IV delivered eNAMPT mAbs were evaluated in our integrated ALI severity scoring system with evaluation of eNAMPT mAbs UU, XX and P in large animal models of ARDS prior to evaluation as a therapeutic strategy in clinical trials for patients with ARDS.Type
textElectronic Thesis
Degree Name
M.S.Degree Level
mastersDegree Program
Graduate CollegeClinical Translational Sciences