This phase 2 proposal is a stratified, placebo controlled, open label, ascending dose Phase 1 study of an anti-C5 (complement component 5) single chain (sc) monoclonal antibody (mAb) derived from bacterial cells, called m5G1.1-scFv, in patients undergoing cardiopulmonary bypass. This single chain monoclonal Ab and its parent m5G1.1mAb block the cleavage of C5 to C5a and C5b, thus inhibiting the pro-inflammatory activities of C5a and preventing the assembly of the membrane attack complex (C5b-C9). Opsonizing activity due to C3b is not inhibited, since it does not block the C3 to C3a and C3b conversion. Cardiopulmonary bypass (CPB) stimulates a widespread inflammatory response, involving activation by the bypass circuit of the complement (C'), kinin, coagulation and fibrinolytic systems. C' activation has been implicated in direct injury of cell membranes and stimulates a wide variety of biochemical and cellular sequelae which may result in activation of blood cells, damage to endothelium and hemolysis. Complement activation during CPB has been well documented and has been postulated to contribute to hemorrhagic syndromes, post perfusion syndrome and pulmonary injury. The human study will enroll 15 patients: 3 placebo and 3 each of 4 doses of m5G1.1-scFv. Doses will be 1/5, 1/2, 1/1, and 2/1 times the biological effective dose as assessed by the ability of the drug to block platelet and leukocyte activation in a simulated extracorporeal circuit model (SEC). Patients with significant infection or C' deficiency are excluded, and clinical, laboratory and pharmacokinetic monitoring will occur intensively pre, during and post CPB. A 4-6 week follow-up is planned. The ultimate goal of this proposal is to use the anti-C5 inhibitor, m5G1.1-scFv , in patients undergoing CPB to attempt to ameliorate complement related damage. A stable, cost effective formulation of m5G1.1-scFv will be manufactured. Preclinical studies, consisting of epitope mapping of m5G1.1-scFv, human tissue cross-reactivity studies, infection susceptibility studies in mice, and in vitro dose-response studies in a SEC model will be performed. Finally, prior to human use, pharmacokinetics/toxicology studies will be performed in 3 chimpanzees.
