COMPLEMENT ACTIVATION AND MYOCARDIAL INFARCTION

Coronary artery disease is associated with extensive morbidity and mortality as well as substantial financial cost. An estimated 11.2 million people in the USA have coronary artery disease that leads to approximately 1.5 million acute myocardial infarctions (AMI) annually. The mechanism by which tissue injury occurs after AMI has not been fully elucidated. However, both animal models and human studies of AMI have demonstrated that complement activation occurs rapidly during AMI and that activated complement components may play a significant role in myocardial damage. The aims of this proposal are to develop and characterize potent soluble complement inhibitors directed against the porcine C5 component of complement as reagents to study the role of complement in AMI. In the Phase I study we propose to (l) isolate the porcine C5 complement component, (2) develop monoclonal antibodies (mAbs) directed against porcine C5, (3) purify and functionally characterize the complement- inhibitor activity of the anti-porcine C5 mAbs, and (4) test the ability of these mAbs to protect porcine endothelial cells from the cytolytic, procoagulant and proinflammatory effects of complement in vitro. If this approach proves to be efficacious, we intend to test the anti-porcine C5 reagents in in vivo models of porcine AMI as a component of the Phase II proposal. In addition, we propose to study the safety and initial efficacy of a humanized monoclonal antibody directed against human C5 in a Phase I setting in AMI patients. Given the potential number of patients who could potentially benefit from a therapeutic agent that blocks tissue damage during AMI, the market for such a product represents a significant commercial opportunity.