(Circulation. 1999;100:2499.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
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
From the Departments of Anesthesiology (J.C.K.F., R.H., P.K., C.R.), Laboratory Medicine (C.R., H.R., B.S.), and Cardiothoracic Surgery (M.D., J.E., G.K., R.S.), Yale University, New Haven, Conn; Department of Anesthesiology (C.D.C., G.S., S.K.S.) and Cardiac Surgery (S.A.), Brigham and Women’s Hospital, Boston, Mass; Biopure Corporation (B.A.), Boston, Mass; Department of Psychiatry, Stanford University (R.O.), Palo Alto, Calif; and Alexion Pharmaceuticals (S.R., L.M., L.L.), New Haven, Conn. Alexion Pharmaceuticals manufactures h5G1.1-scFv, the drug that was studied in this investigation.
Correspondence to Jane C.K. Fitch, MD, Department of Anesthesiology, Baylor College of Medicine, 6550 Fannin, Suite 1003, Houston, TX 77030. E-mail jfitch{at}bcm.tmc.edu
Background—Cardiopulmonary bypass (CPB) induces a systemic inflammatory response that causes substantial clinical morbidity. Activation of complement during CPB contributes significantly to this inflammatory process. We examined the capability of a novel therapeutic complement inhibitor to prevent pathological complement activation and tissue injury in patients undergoing CPB.
Methods and Results—A humanized, recombinant, single-chain antibody specific for human C5, h5G1.1-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-life from 7.0 to 14.5 hours. Pharmacodynamic analysis demonstrated significant dose-dependent inhibition of complement hemolytic activity for up to 14 hours at 2 mg/kg. The generation of proinflammatory complement byproducts (sC5b-9) was effectively inhibited in a dose-dependent fashion. Leukocyte activation, 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 myocardial injury (creatine kinase–MB release, P=0.05) in patients who received 2 mg/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 1-U reduction in postoperative blood loss (P<0.05) in patients who received 1 or 2 mg/kg.
Conclusions—A single-chain antibody specific for human C5 is a safe and effective inhibitor of pathological complement activation in patients undergoing CPB. In addition to significantly reducing sC5b-9 formation and leukocyte CD11b expression, C5 inhibition significantly attenuates postoperative myocardial injury, cognitive deficits, and blood loss. These data suggest that C5 inhibition may represent a novel therapeutic strategy for preventing complement-mediated inflammation and tissue injury.
Key Words: cardiopulmonary bypass • inflammation • proteins • immunology
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