PBEF Neutralizing Humanized Monoclonal Antibodies As Novel Therapeutic Approaches

描述(由申请人提供)：大约40-60%住进重症监护病房(ICU)的患者需要机械通气合并急性肺损伤(ALI)，这是一种常见的诊断，要求插管并放置在呼吸机上。现在已经很好地认识到，VILI的发展直接导致了与ALI相关的令人无法接受的高死亡率，尽管在通风策略方面取得了进展，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、炎性细胞内流增多和促炎细胞因子表达增强等共同的病理特征。目前，唯一的补救措施是使用低潮气量呼吸机，这一做法并未得到普遍接受，不足以完全预防VILI。我们以前的工作已经确定PBEF是一种聚集在肺液中的炎性细胞因子，是介导ALI/VILI损害的主要潜在因素之一。我们还进行了原理验证研究，以证明中和抗PBEF的多克隆抗体时，无论是气管内还是静脉注射，都能显著减少ALI/VILI小鼠模型的发生率。因此，我们建议制备人源化的ANT-PBEF单抗(P-BEFizumab)，可用于ALI/VILI患者的预防和治疗。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，以及在战线和生物治疗情况下，如化学或神经毒素中毒。 与公共卫生相关：急性肺损伤是一种极其虚弱的疾病，死亡率很高(35-40%)，而且差异很大，因为老年人、非洲裔和拉丁裔患者特别容易受到这种疾病的破坏。患者需要机械通气来克服严重的缺氧和呼吸衰竭，不幸的是，这会加剧肺损伤。我们已经证明PBEF是一个主要的影响因素，并建议产生治疗性的人源化中和抗PBEF单抗来治疗急性肺损伤患者。

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.