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

重症监护病房(ICU)的死亡率高得令人无法接受，而且与病程直接相关 支持呼吸衰竭患者所需的机械通风。例如，急性呼吸道疾病 窘迫综合征(ARDS)是一种令人头痛的急性炎症性肺部疾病，需要机械呼吸。 由于严重的低氧血症和呼吸衰竭而导致的支持。估计每年有200,000例ARDS病例(美国) 呼吸机诱导的肺损伤(VILI)的死亡率为30-40%，这是一种强烈的肺部炎症刺激因素 和释放多种炎性细胞因子(称为细胞因子风暴)，这是导致 不良反应的严重程度和死亡率。VILI也可继发于机械通气的呼吸衰竭患者 重症监护病房(ICU)，即使ARDS不存在。因为在ICU中没有临床治疗干预 虽然已经大大解决了VILI问题，但VILI的有效预防性治疗的需求仍然严重未得到满足。 Aquung治疗公司的科学家发现烟酰胺磷酸核糖转移酶(NAMPT)是一种 VILI发展中的新上游治疗靶点，并已开发出人源性单抗 (FABS或片段抗原结合)，旨在中和循环细胞外NAMPT(或eNAMPT)。 由于缺乏已获批准的VILI疗法，ALT试图通过开发人类单克隆来改善ICU的预后 FAB，eNamptor™，作为减少或消除VILI的创新策略，目标是循环中的eNAMPT。 危重病人接受机械插管时预防性给予E-™ 与以前的ICU策略相比，这是一个明显的优势。我们预计eNamptor™将减少或 消除VILI的发生率和严重性，减少ICU患者需要机械通气的天数， 降低医疗成本，提高ICU存活率。在此背景下，这一STTR第一阶段/第二阶段的目标是快速 跟踪应用是评价NAMPT中和聚乙二醇化和非聚乙二醇化的人单抗eNamptor™ Fab在减弱eNAMPT诱导的NFkB体外信号转导和临床前作用的候选药物 小鼠VILI活体模型(STTRI期)。此外，我们将进行药代动力学/药效学和 在大鼠和犬模型中使用™候选抗体进行的毒理学研究(STTRII期)。本STTR 第一阶段/第二阶段Fast Track应用程序代表生物技术初创公司(Aquung)之间的合作 治疗公司)、一个学术实体(亚利桑那大学)和一家私营公司(Gennova生物制药公司 有限公司)。我们将共同解决一个严重而重要的未得到满足的需求，通过验证eNamptor™作为 可行的VILI治疗方法。我们预计这些努力将导致将IND申请提交给 美国食品和药物管理局将推广eNamptor™作为男性VILI的治疗策略。

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.