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，其是通过凝集素途径激活补体所独特需要的，并且可能是开发新型治疗剂的有吸引力的靶标。MASP-2也是血浆中丰度最低的补体蛋白之一，并且为凝集素介导的补体活化提供了潜在的限速靶标。一般认为，补体系统可以通过三种不同的酶级联激活，称为经典途径、旁路途径和凝集素途径。补体系统是重要的宿主防御机制;然而，大量补体激活可引发强烈的炎症反应，其被认为有助于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），期望开发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的途径特异性治疗剂。最近发表的研究，从我们的合作者之一的实验室使用大鼠模型牵连的凝集素途径在心肌缺血/再灌注损伤的发病机制。已经开发了MASP-2蛋白遗传缺陷的小鼠。由于MASP-2（-/-）小鼠缺乏MASP-2自身抗原，因此其是用于杂交瘤开发程序以鉴定抑制性抗MASP-2 MAb的优选动物，并且此类程序目前正在进行中。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/再灌注损伤中起主要病理作用。在该1期研究中，我们的具体目标是当在MIRP的鼠模型中评价MASP-2（-/-）和匹配的MASP（+/+）小鼠时比较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.