Rheumatoid arthritis (RA) is a severely debilitating disease that affects approximately 0.5-1% of the population. Currently, the most effective treatment for this disease involves the use of one of several anti-TNF agents either alone or in combination with methotrexate. However, significant side effects are associated with this treatment, most notably the risk of increased infections which cannot be tolerated by some patients. Therefore, there is a need for an effective alternative treatment for this disease with an agent directed at a novel target in the flammatory cascade. The goal of the research proposed here is to determine whether MBL-associated serine protease (MASP-2), an essential component of the lectin-activated complement pathway, may be such ? a target. Omeros has developed a strong proprietary program around the use of MASP-2 antagonists for the treatment of a variety of acute and chronic inflammatory conditions. Omeros has established an ongoing collaboration with Dr. William Schwaeble (University of Leister, U.K.) who was the first to clone human MASP-2 in collaboration with other research colleagues. .Dr. Schwaeble has subsequently co-authored many publications focused on the molecular biology and biochemistry of MASP-2 and other lectin pathway components. As part of our joint collaboration, patent applications have been filed with Dr. Schwaeble and Omeros on the therapeutic utility of inhibitors of MASP-2 for various acute and chronic inflammatory conditions. We have initiated the development of blocking antibodies to MASP-2 that can be used for proof of principle studies in appropriate inflammatory animal models. The long-term goal of this program is to develop monoclonal antibodies (MoAbs) capable of blocking human MASP-2 function as potential therapeutic agents. We present preliminary data that suggest that MASP-2 -/- mice on a C57Bl/6 background are less susceptible than their wild-type litter mate controls to developing inflammation in an antibody-induced model of RA, thereby indicating the potential utility of MASP-2 antagonists for the treatment of RA. There was a clear and consistent reduction in both the clinical and histological scores in the MASP-2 -/- mice. However, only a mild arthritic response was observed in the wild-type animals and C57BL/6 mice are known to show a poor response in this ? RA disease model. We are currently backcrossing the MASP-2 -/- mice into the DBA/1 background which is highly susceptible to both the antibody-induced arthritis as well as collagen-induced arthritis. Therefore, the goal of the research proposed here is to determine whether MASP-2 -/- mice that have been backcrossed into the DBA/1 background develop less severe disease than their wild-type litter mate controls in either the antibody-induced or the collagen-induced arthritis models. Results from these studies should demonstrate whether MASP-2 is a promising novel target for the treatment of RA. ? ? ?
