PBEF Neutralizing Humanized Monoclonal Antibodies As Novel Therapeutic Approaches

描述（由申请人提供）：大约40-60%入住重症监护病房（ICU）的患者需要急性肺损伤（ALI）机械通气，这是一种常见的诊断，要求插管和放置呼吸机。现在人们普遍认识到，VILI的发展直接导致了与ALI相关的不可接受的高死亡率，尽管通气策略取得了进展，VILI仍然是ICU的一个主要问题。VILI和ALI具有明显的肺毛细血管渗漏、炎症细胞内流增加和促炎细胞因子表达增强等共同病理特征。目前，唯一的补救措施是使用低潮气量通风，这种做法没有得到普遍接受，也不足以完全预防VILI。我们之前的工作已经确定PBEF是一种积聚在肺液中的炎症细胞因子，是介导ALI/VILI损伤的主要潜在因素之一。我们还进行了原理验证研究，证明在气管内和静脉内施用PBEF的中和多克隆抗体可显著减少小鼠ALI/VILI模型。因此，我们建议产生人源化抗pbef单克隆抗体（P- BEFizumab），可作为ALI/VILI患者的预防和治疗药物。一旦这些抗体在治疗ALI/VILI患者方面的可信度得到确立，我们相信这些抗体也将用于其他肺部疾病，如慢性阻塞性肺疾病，以及战场情况，如战争前线和生物威胁情况，如化学或神经毒素中毒。

DESCRIPTION (provided by applicant): Approximately 40-60% of patients admitted to intensive care units (ICU) require mechanical ventilation with acute lung injury (ALI) a common diagnosis which mandates intubation and placement on the ventilator. It is now well recognized that the development of VILI directly contributes to the unacceptably high mortality rate associated with ALI and despite the advances in ventilation strategies, VILI remains a major problem in ICU. VILI and ALI have common pathological features such as marked pulmonary capillary leakage, increased inflammatory cell influx and enhanced pro-inflammatory cytokine expression. Currently, the only remedial procedure in place is the use of low tidal volume ventilation, a practice not universally embraced and insufficient to completely prevent VILI. Our previous work has identified PBEF, an inflammatory cytokine that accumulates in the lung fluid as one of the major underlying factors that mediated the damage seen in ALI/VILI. We also carried out proof-of-principle studies to demonstrate that neutralizing polyclonal antibodies against PBEF when administered intratracheally and also intravenously has significant reduction in mouse model of ALI/VILI. We therefore propose to generate humanized ant-PBEF monoclonal antibodies (P- BEFizumab) that can be used as both prophylactic and therapeutic agents in patients with ALI/VILI. Once the credibility of these antibodies in treating patients with ALI/VILI is established, we believe that these antibodies will also be useful in other lung disorders such as chronic obstructive pulmonary disorders and also in field situations such as the war front and biothreat situations like chemical or neurotoxin poisoning. PUBLIC HEALTH RELEVANCE: Acute lung injury is an extremely debilitating disease with a high mortality rate (35-40%) and with significant disparities as the elderly, African-descent and Latino patients are particularly susceptible to the ravages of this disease. Patients require mechanical ventilation to overcome severe hypoxia and respiratory failure and unfortunately, it can exacerbate the lung injury. We have shown PBEF as a major contributing factor, and propose to generate therapeutic humanized neutralizing anti-PBEF monoclonal antibodies to treat patients with acute lung injury.