Protease Resistant C1 Inhibitor for Sepsis

Activation of both the complement and the contact systems of intrinsic coagulation are implicated ipathophysiology of sepsis. C1-inhibitor (C1-INH) is a member of the superfamily of serine protease ithe major inhibitor of both factor XIIa and kallikrein of the contact system and also the only knownC1s and C1r from the classical pathway of complement. Thus, C1-INH regulates the activity of two plathat form biologically active peptides, i.e. the anaphylatoxins C5a, C3a and C4a (the order correspoactivities), and bradykinin, which is known for its vasodilating and vasopermeability enhancing effeis a major regulator of inflammatory reactions. Preliminary data suggest that because C1-INH regulatcascade systems it has therapeutic potential for sepsis. Because C1-INH is inactivated by inflammatoneutrophil elastase a protease resistant mutant C1-INH has been generated for therapeutic use. In phand purify sufficient quantities of this recombinant protease- resistant C1-INH (rPR-C1-INH) for aniactivity of the rPR-C1-INH will be characterized using various in vitro assays and its activity willmodel of endotoxemia. In Phase II we will produce sufficient quantities of rPR-C1-INH to evaluate efsepsis model and begin preclinical development if primate studies are promising. This protease-resistherapeutic potential for conditions associated with excessive activation of the contact and complembums, sepsis and ARDS.