MASP-2 MoAB therapeutics for MI/RP injury
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.
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