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

Circulation. 1999 Dec 21-28;100(25):2499-506. doi: 10.1161/01.cir.100.25.2499.

Abstract

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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Blood Loss, Surgical
  • Cardiopulmonary Bypass*
  • Cognition Disorders / epidemiology
  • Cognition Disorders / prevention & control
  • Complement Activation
  • Complement C5 / antagonists & inhibitors*
  • Complement C5 / immunology
  • Complement Membrane Attack Complex / immunology*
  • Coronary Artery Bypass*
  • Coronary Disease / surgery*
  • Creatine Kinase / blood
  • Humans
  • Inflammation / prevention & control
  • Isoenzymes
  • Middle Aged
  • Myocardial Reperfusion Injury / immunology
  • Myocardial Reperfusion Injury / prevention & control*
  • Postoperative Complications / epidemiology
  • Postoperative Complications / prevention & control
  • Prospective Studies
  • Psychological Tests
  • Single-Chain Antibodies

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Complement C5
  • Complement Membrane Attack Complex
  • Isoenzymes
  • Single-Chain Antibodies
  • pexelizumab
  • Creatine Kinase