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% 入住重症监护病房 (ICU) 的患者需要机械通气，并患有急性肺损伤 (ALI)，这是一种常见的诊断，要求插管并使用呼吸机。现在人们普遍认识到，VILI 的发展直接导致了与 ALI 相关的令人难以接受的高死亡率，尽管通气策略取得了进步，但 VILI 仍然是 ICU 的一个主要问题。 VILI和ALI具有共同的病理特征，如明显的肺毛细血管渗漏、炎症细胞流入增加和促炎细胞因子表达增强。目前，唯一的补救措施是使用低潮气量通气，这种做法并未得到普遍接受，也不足以完全预防 VILI。我们之前的工作已确定 PBEF（一种在肺液中积聚的炎症细胞因子）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，以证明在气管内和静脉内施用时，针对 PBEF 的中和多克隆抗体可以显着减少小鼠模型的 ALI/VILI。因此，我们建议生产人源化 ant-PBEF 单克隆抗体（P-BEFizumab），可用作 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可用于治疗其他肺部疾病，例如慢性阻塞性肺疾病，也可用于战场情况，例如战争前线和化学武器等生物威胁情况。或神经毒素中毒。