Novel Therapeutic Antibody Targeting of Extracellular NAMPT in Ventilator-Induced Lung Injury (VILI)

呼吸机引起的肺损伤 (VILI) 中细胞外 NAMPT 的新型治疗抗体

• 批准号: 10026453
• 负责人: Joe G. N. Garcia
• 金额: $ 75万
• 依托单位: AQUALUNG THERAPEUTICS CORP.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026453
• 关键词: Acute; Address; Adult Respiratory Distress Syndrome; Affect; Affinity; Alveolar; Antibodies; Arizona; Attenuated; Avidity; Biological Products; Biotechnology; Canis familiaris; Caring; Cells; Clinical; Clinical Research; Clinical Trials; Collaborations; Contracts; Critical Care; Critical Illness; Development; Drug Kinetics; Exhibits; FDA approved; Fab Immunoglobulins; Floods; Goals; Half-Life; Health Care Costs; Human; Human Resources; Hypoxemia; In Vitro; Incidence; Inflammatory; Intensive Care Units; Intubation; Investigational Drugs; Lead; Libraries; Ligands; Lung; Lung Inflammation; Mechanical ventilation; Mechanics; Modeling; Morbidity - disease rate; Mus; New Drug Approvals; Outcome; Patients; Phage Display; Pharmacodynamics; Pharmacology Study; Pharmacology and Toxicology; Phase; Preventive therapy; Privatization; Protocols documentation; Rattus; Respiratory Failure; Scientist; Severities; Signal Transduction; Small Business Technology Transfer Research; Stimulus; TLR4 gene; Therapeutic; Therapeutic Intervention; Therapeutic antibodies; Time; Toxicology; United States; Universities; Vascular Permeabilities; Ventilator-induced lung injury; Work; cytokine; cytokine release syndrome; design; extracellular; human monoclonal antibodies; immunogenic; improved; in vivo; in vivo Model; inflammatory lung disease; innovation; lung injury; man; meetings; mortality; neutralizing antibody; nicotinamide phosphoribosyltransferase; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; pre-clinical; prevent; prophylactic; public health relevance; success; therapeutic target; ventilation

Mortality rates in intensive care units (ICUs) are unacceptably high and are directly related to the duration of mechanical ventilation that is required to support patients with respiratory failure. For example, acute respiratory distress syndrome (ARDS) is a vexing acute inflammatory lung disease requiring mechanical ventilatory support as the result of severe hypoxemia and respiratory failure. The estimated 200,000 ARDS cases/yr (U.S.) exhibit a mortality rate of 30-40% with ventilator-induced lung injury (VILI), a potent stimulus for lung inflammation and release of multiple inflammatory cytokines (known as cytokine storm), a significant contributor to ARDS severity and mortality. VILI may also ensue in mechanically ventilated patients with respiratory failure in intensive care units (ICUs) even when ARDS is not present. As no clinical therapeutic intervention in the ICU has significantly addressed VILI, there remains a serious unmet need for effective preventive therapies for VILI. Aqualung Therapeutics scientists have identified nicotinamide phosphoribosyltransferase (NAMPT) as a novel upstream therapeutic target in the development of VILI, and have developed human monoclonal antibodies (Fabs or fragment antigen-binding) designed to neutralize circulating extracellular NAMPT (or eNAMPT). Given the lack of approved VILI therapies, ALT seeks to improve ICU outcomes by developing the human monoclonal Fab, eNamptor™, as an innovative strategy to reduce or eliminate VILI, targeting circulating eNAMPT. eNamptor™ will be given prophylactically at the time of intubation in critically ill ICU patients receiving mechanical ventilation, a marked advantage compared with prior ICU strategies. We expect that eNamptor™ will reduce or eliminate VILI incidence and severity, reduce the number of days ICU patients require mechanical ventilation, reduce healthcare costs, and improve ICU survival. With this background, the goal of this STTR Phase I/II Fast Track application is to evaluate NAMPT-neutralizing pegylated and non-pegylated human monoclonal eNamptor™ Fab candidates for efficacy in attenuating eNAMPT-induced NFkB in vitro signaling and preclinical murine VILI in vivo models (STTR Phase I). In addition, we will conduct pharmacokinetic/pharmacodynamic and toxicology studies with lead eNamptor™ Fab candidates in rat and canine models (STTR Phase II). This STTR Phase I/II Fast Track application represents a collaboration between a biotech startup company (Aqualung Therapeutics Corporation), an academic entity (University of Arizona) and a private company (Gennova Biopharmaceutical Ltd.). Together, we will address a serious and important unmet need by validating eNamptor™ as a viable VILI therapeutic approach. We anticipate these efforts will lead to submission of a IND application to the FDA to promote eNamptor™ as a therapeutic strategy for VILI in man.

重症监护病房的死亡率（ICU）不可接受，与持续时间直接相关 支持呼吸衰竭患者所需的机械通气。例如，急性呼吸道 遇险综合征（ARDS）是一种烦人的急性炎症肺疾病，需要机械通气 由于严重的低氧血症和呼吸衰竭而导致的支持。估计有200,000箱/年（美国） 呼吸机诱导的肺损伤（VILI）的死亡率为30-40％，这是肺损伤的潜在刺激 并释放多种炎症性细胞因子（称为细胞因子风暴），这是一个重要的贡献者 严重和死亡率。 VILI也可能需要机械通风的患者 即使不存在ARDS，重症监护病房（ICU）也是如此。由于没有ICU的临床治疗干预 已经显着解决了Vili，对VILI有效预防疗法仍然存在严重的未满足。 Aqualung Therapeutics科学家已经确定烟酰胺磷酸蛋白酶基转移酶（NAMPT）为 新型上游治疗靶标在VILI的发展中，并开发了人类单克隆抗体 （Fabs或碎片抗原结合）旨在中和循环外细胞外NAMPT（或ENAMPT）。 鉴于缺乏批准的VILI疗法，ALT试图通过开发人类单克隆来改善ICU的结果 Fab，Enamptor™，作为减少或消除Vili的创新策略，以循环enampt为目标。 ENAMPTOR™将在接受机械的重症ICU患者的插管时进行预防。 通风，与先前的ICU策略相比，这是一个明显的优势。我们希望Enamptor™会减少或 消除VILI事件和严重程度，减少ICU患者需要机械通气的天数， 降低医疗保健成本，并提高ICU生存。在此背景下，该sttr I/II的目标很快 轨道应用是评估NAMPT中和质量和非垂直的人类单克隆enamptor™ Fab候选物，以衰减ENAMPT引起的NFKB体外信号和临床前的效率 鼠体内模型（STTR I）。此外，我们将进行药代动力学/药效学和 用大鼠和犬模型中的Lead Enamptor™Fab候选物进行毒理学研究（STTR II期）。这个sttr I/II阶段快速应用程序代表了一家生物技术初创公司（Aqualung）之间的合作 Therapeutics Corporation），一家学术实体（亚利桑那大学）和一家私人公司（Gennova Biopharmaceutical Ltd.）。我们将通过验证Enamptor™作为一个认真而重要的未满足需求来解决 可行的Vili治疗方法。我们预计这些努力将导致向IND申请提交给 FDA将Enamptor™作为人类Vili的治疗策略促进。