MASP-2 MoAB therapeutics for MI/RP injury

描述(由申请人提供)：总体目标是开发能够阻断人MASP-2功能的单抗，作为潜在的心肌缺血/再灌注损伤的治疗剂。MASP-2是一种血浆丝氨酸蛋白酶，通过凝集素途径激活补体是唯一必需的，可能是新疗法开发的一个有吸引力的靶点。MASP-2也是血浆中含量最低的补体蛋白之一，为凝集素介导的补体激活提供了一个潜在的限速靶点。人们普遍认为补体系统可以通过三个不同的酶途径激活，即经典途径、替代途径和凝集素途径。补体系统是一种重要的宿主防御机制；然而，大量的补体激活可以触发强烈的炎症反应，这被认为是许多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)，人们希望开发一种途径特异性的治疗药物，这种药物只抑制导致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一项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经被培育出来。由于MASP-2(-/-)小鼠缺乏MASP-2“自身抗原，因此MASP-2(-/-)小鼠是鉴定抑制性抗MASP-2单抗杂交瘤的首选动物。MASP-2(-/-)小鼠将提供一个独特而有价值的研究工具，以确定凝集素途径是否在心肌缺血/再灌注损伤中起重要的病理作用。在这项第一阶段的研究中，我们的具体目标是比较MASP-2(-/-)和匹配的MASP(/)小鼠在MIRP小鼠模型中的心脏和炎症功能结果。

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.