PBEF Neutralizing Humanized Monoclonal Antibodies As Novel Therapeutic Approaches

PBEF 中和人源化单克隆抗体作为新型治疗方法

• 批准号: 8320121
• 负责人: Joe G.N. Garcia
• 金额: $ 31.03万
• 依托单位: AQUALUNG THERAPEUTICS, CORP
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320121
• 关键词: Acute Lung Injury; Address; African; Alveolar; Animal Model; Antibodies; Ants; Asthma; Attenuated; Biological; Biological Markers; Blood capillaries; Candidate Disease Gene; Cardiac Surgery procedures; Cells; Chemicals; Chronic; Cloning; Critical Illness; Data Reporting; Development; Diagnosis; Disease; Elderly; Environmental air flow; Europe; Extravasation; FDA approved; Future; Generations; Genes; Genetic Polymorphism; Goals; Hamman-Rich syndrome; Human; Human Cell Line; Hybridomas; Hypoxia; IgG4; Immunoglobulins; Individual; Infection; Inflammation Mediators; Inflammatory; Intensive Care Units; Intubation; Latino; Lead; Light; Liquid substance; Lung; Lung diseases; Marketing; Mechanical Ventilators; Mechanical ventilation; Mediating; Mediator of activation protein; Medical; Modeling; Monoclonal Antibodies; Mus; Neurotoxins; Operative Surgical Procedures; Organ Transplantation; Outcome; Pathologic; Patients; Pharmaceutical Preparations; Phase; Poisoning; Pre-Clinical Model; Procedures; Production; Protocols documentation; Pulmonary Hypertension; Respiratory Failure; Risk; Sarcoidosis; Sepsis; Severities; Sickle Cell Anemia; Solid; Structure of parenchyma of lung; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Tidal Volume; TimeLine; Trauma; Vascular Permeabilities; Ventilator; Ventilator-induced lung injury; War; Work; attenuation; base; biothreat; capillary; combat; commercial application; cytokine; humanized antibody; humanized monoclonal antibodies; innovation; lung injury; mortality; mouse model; neutralizing antibody; neutrophil; novel; novel therapeutic intervention; phase 2 study; polyclonal antibody; pre-B-cell colony-enhancing factor protein; pre-clinical; prevent; promoter; prophylactic; therapeutic target

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.

描述（由申请人提供）：大约40-60％的接受重症监护病房（ICU）的患者需要用急性肺损伤（ALI）进行机械通气（ALI）一种常见诊断，该诊断要求在呼吸机上进行插管和放置。现在已经众所周知，VILI的发展直接导致了与Ali相关的高死亡率，尽管通风策略取得了进步，但VILI仍然是ICU的主要问题。 VILI和ALI具有常见的病理特征，例如明显的肺毛细血管泄漏，炎症细胞的涌入增加和增强的促炎细胞因子表达。目前，唯一的补救程序是使用低潮汐量通风，这种做法不普遍接受，不足以完全防止Vili。我们以前的工作已经确定了PBEF，这是一种在肺液中积累的炎性细胞因子，是介导ALI/VILI损害的主要潜在因素之一。我们还进行了原理学证明，以证明当摄入气管内施用时中和对PBEF的多克隆抗体，并且静脉内静脉内对ALI/VILI小鼠模型的静脉注射显着降低。因此，我们建议在ALI/VILI患者中生成人源化的ANT-PBEF单克隆抗体（p- befizumab），既可以用作预防性和治疗剂。一旦建立了这些抗体在治疗ALI/VILI患者方面的可信度，我们认为这些抗体在其他肺部疾病中也将有用，例如慢性阻塞性肺部疾病，以及战争局部和诸如野生动物的现场情况，例如化学或神经毒素中毒。