PBEF Neutralizing Humanized Monoclonal Antibodies As Novel Therapeutic Approaches

描述（由申请人提供）：大约40-60%的重症监护室（ICU）患者需要机械通气，急性肺损伤（ALI）是一种常见的诊断，需要插管和放置呼吸机。现在公认VILI的发展直接导致与ALI相关的不可接受的高死亡率，尽管通气策略取得了进展，但VILI仍然是ICU的主要问题。VILI和ALI具有共同的病理特征，如显著的肺毛细血管渗漏、增加的炎性细胞内流和增强的促炎细胞因子表达。目前，唯一的补救措施是使用低潮气量通气，这种做法并不普遍接受，也不足以完全预防VILI。我们以前的工作已经确定了PBEF，一种在肺液中积累的炎性细胞因子，是介导ALI/VILI中观察到的损伤的主要潜在因素之一。我们还进行了原理验证研究，以证明当经气管内和静脉内施用时，抗PBEF的中和多克隆抗体在ALI/VILI的小鼠模型中具有显著的减少。因此，我们提出产生人源化抗PBEF单克隆抗体（P-BEFizumab），其可用作ALI/VILI患者的预防剂和治疗剂。一旦这些抗体在治疗患有ALI/VILI的患者中的可信度被确立，我们相信这些抗体也将在其他肺部疾病如慢性阻塞性肺病中以及在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中有用。

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.