MASP-2 MoAB therapeutics for MI/RP injury

MASP-2 MoAB 治疗 MI/RP 损伤

• 批准号: 6991686
• 负责人: CLARK E TEDFORD
• 金额: $ 12.7万
• 依托单位: OMEROS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6991686
• 关键词: cardiovascular agents; cell migration; cytokine; disease /disorder model; drug design /synthesis /production; enzyme inhibitors; genetically modified animals; immunologic substance development /preparation; laboratory mouse; monoclonal antibody; myocardial ischemia /hypoxia; neutrophil; pathologic process; reperfusion; serine proteinases; therapy adverse effect

DESCRIPTION (provided by applicant): The overall goal is to develop monoclonal antibodies capable of blocking human MASP-2 function as potential therapeutic agents for myocardial ischemia/reperfusion injury. MASP-2 is a plasma serine protease uniquely required for complement activation via the lectin pathway and may be an attractive target for the development of novel therapeutics. MASP-2 is also one of the least abundant complement proteins in plasma, and provides a potential rate-limiting target for lectin-mediated complement activation. It is generally accepted that the complement system can be activated through three distinct enzymatic cascades, referred to as the classical, alternative and lectin pathways. The complement system is an important host defense mechanism; however, massive complement activation can trigger an intense inflammatory response that is thought to contribute to the pathogenesis of numerous disease states, including myocardial ischemia/reperfusion injury. To treat myocardial ischemia/reperfusion injury (MIRP) it would be desirable to develop pathway-specific therapeutic agents that inhibit only the complement pathway causing the particular pathology without completely shutting down the host defense capabilities of complement. Recent published studies from the laboratory of one of our collaborators using a rat model implicate the lectin pathway in the pathogenesis of myocardial ischemia/reperfusion injury. A mouse genetically-deficient in the MASP-2 protein has been developed. Since the MASP-2 (-/-) mouse lacks the MASP-2 "self antigen, it is the preferred animal to use in a hybridoma development program to identify inhibitory anti-MASP-2 MAbs and such a program is currently underway. The MASP-2 (-/-) mouse will provide a unique and valuable research tool to establish if the lectin pathway plays a major pathological role in myocardial ischemia/reperfusion injury. In this Phase 1 study our specific objectives are to compare cardio and inflammatory functional outcomes when both MASP-2 (-/-) and matched MASP(+/+) mice are evaluated in a murine model of MIRP.

描述（由申请人提供）：总体目标是开发能够阻断人MASP-2功能的单克隆抗体，作为心肌缺血/再灌注损伤的潜在治疗剂。 MASP-2 是一种血浆丝氨酸蛋白酶，是通过凝集素途径激活补体所必需的，并且可能是开发新型疗法的一个有吸引力的靶标。 MASP-2 也是血浆中最丰富的补体蛋白之一，并为凝集素介导的补体激活提供潜在的限速靶标。人们普遍认为补体系统可以通过三种不同的酶级联被激活，称为经典途径、替代途径和凝集素途径。补体系统是重要的宿主防御机制；然而，大量的补体激活会引发强烈的炎症反应，这被认为是导致多种疾病状态的发病机制，包括心肌缺血/再灌注损伤。为了治疗心肌缺血/再灌注损伤(MIRP)，需要开发途径特异性治疗剂，其仅抑制引起特定病理的补体途径，而不完全关闭补体的宿主防御能力。我们的一位合作者的实验室最近发表的使用大鼠模型的研究表明，凝集素途径与心肌缺血/再灌注损伤的发病机制有关。一种 MASP-2 蛋白基因缺陷的小鼠已被开发出来。由于 MASP-2 (-/-) 小鼠缺乏 MASP-2“自身抗原，因此它是用于鉴定抑制性抗 MASP-2 MAb 的杂交瘤开发计划的首选动物，并且此类计划目前正在进行中。 MASP-2 (-/-) 小鼠将提供独特且有价值的研究工具，以确定凝集素途径是否在心肌缺血/再灌注损伤中发挥主要病理作用。在这一阶段的研究中，我们的具体目标是比较心脏和心肌损伤。在 MIRP 小鼠模型中评估 MASP-2 (-/-) 和匹配的 MASP(+/+) 小鼠时的炎症功能结果。