Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass

Background-Cardiopulmonary bypass (CPB) induces a systemic inflammatory res ponse that causes substantial clinical morbidity. Activation of complement during CPB contributes significantly to this inflammatory process. We exami ned the capability of a novel therapeutic complement inhibitor to prevent p athological complement activation and tissue injury in patients undergoing CPB. Methods and Results-A humanized, recombinant, single-chain antibody specifi c for human C5, hSGI.1-scFv, was intravenously administered in 1 of 4 doses ranging from 0.2 to 2.0 mg/kg before CPB. h5G1.1-scFv was found to be safe and well tolerated. Pharmacokinetic analysis revealed a sustained half-lif e from 7.0 to 14.5 hours. Pharmacodynamic analysis demonstrated significant dose-dependent inhibition of complement hemolytic activity for up to 14 ho urs at 2 mg/kg. The generation of proinflammatory complement byproducts (sC 5b-9) was effectively inhibited in a dose-dependent fashion. Leukocyte acti vation, as measured by surface expression of CD11b, was reduced (P<0.05) in patients who received 1 and 2 mg/kg. There was a 40% reduction in myocardi al injury (creatine kinase-MB release, P=0.05) in patients who received 2 m g/kg. Sequential Mini-Mental State Examinations (MMSE) demonstrated an 80% reduction in new cognitive deficits (P<0.05) in patients treated with 2 mg/ kg. Finally, there was a I-U reduction in postoperative blood loss (P<0.05) in patients who received I or 2 mg/kg. Conclusions-A single-chain antibody specific for human C5 is a safe and eff ective inhibitor of pathological complement activation in patients undergoi ng CPB. In addition to significantly reducing sC5b-9 formation and leukocyt e CD11b expression, C5 inhibition significantly attenuates postoperative my ocardial injury, cognitive deficits, and blood loss. These data suggest tha t C5 inhibition may represent a novel therapeutic strategy for preventing c omplement-mediated inflammation and tissue injury.