Reperfusion Injury Therapy: Role for IgM Antibody

再灌注损伤治疗：IgM 抗体的作用

• 批准号: 6549434
• 负责人: ELISABETH M CARROLL
• 金额: $ 21.59万
• 依托单位: DECLMMUNE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2004-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6549434
• 关键词: biotherapeutic agent; drug design /synthesis /production; hybridomas; immunoglobulin M; immunologic substance development /preparation; ischemia; laboratory mouse; monoclonal antibody; phosphatidylcholines; reperfusion

DESCRIPTION (provided by applicant): Ischemia and reperfusion is one of the major mechanisms underlying human disease. Ischemia occurs when the arterial or oxygenated blood supply is interrupted to an organ or tissue. Reperfusion refers to the reestablishment of blood flow after the period of ischemia. Studies in rodents and large animals demonstrate that the complement system is a major mediator of ischemia-reperfusion injury in various tissues including myocardium, central nervous system, intestine and hindlimb. Our recent results identified natural IgM antibody as the initial step in complement-dependent injury. This phase I application proposes two specific aims: (1) determine the feasibility of identification of specific B-1 cell hybridomas that secrete pathogenic IgM; (2) examine the feasibility of identifying peptides that bind to the specific IgM antibodies that initiate injury. Successful completion of phase I will lead to phase II which will test the proof-of-concept that mutant IgM (does not bind complement) and/or peptides that bind IgM will block reperfusion injury in vivo. Reperfusion injury is a documented major mechanism of injury following heart attack or coronary events, stroke and trauma estimated to affect over 13 million patients per year and representing a $ 3.5 billion market. Currently, there are no effective treatments for blocking injury. Development of a specific inhibitor of reperfusion injury at the earliest stage of inflammation would provide an important medical benefit. The identification of an inhibitor/s that act at the induction stage of injury would have broad commercial application given the many types of tissues affected by reperfusion injury. The identification of hybridoma clones, which secrete antibody that initiates injury, or specific inhibitors of endogenous IgM will provide an important basis for development of future therapie.

描述（由申请人提供）：缺血再灌注是人类疾病的主要机制之一。当一个器官或组织的动脉或含氧血液供应中断时，就会发生缺血。再灌注是指缺血期后血流的重建。对啮齿动物和大型动物的研究表明，补体系统是心肌、中枢神经系统、肠道和后肢等多种组织缺血再灌注损伤的主要介质。我们最近的结果确定天然IgM抗体是补体依赖性损伤的第一步。该I期申请提出了两个具体目标：(1)确定鉴定分泌致病性IgM的特异性B-1细胞杂交瘤的可行性；(2)研究鉴定与引发损伤的特异性IgM抗体结合的肽的可行性。I期研究的成功完成将导致II期的研究，II期将测试突变型IgM（不结合补体）和/或结合IgM的肽在体内阻断再灌注损伤的概念验证。再灌注损伤是心脏病发作或冠状动脉事件、中风和创伤后的主要损伤机制，估计每年影响超过1300万患者，代表35亿美元的市场。目前，对于闭塞性损伤尚无有效的治疗方法。在炎症的早期阶段开发特异性的再灌注损伤抑制剂将提供重要的医学益处。考虑到受再灌注损伤影响的组织类型很多，确定在损伤诱导阶段起作用的抑制剂将具有广泛的商业应用。杂交瘤克隆可分泌引发损伤的抗体或内源性IgM特异性抑制剂，其鉴定将为未来治疗的发展提供重要基础。