title: 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.
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.
  
  
  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.
authors.affiliation: Department of Anesthesiology, Yale University, New Haven, CT, USA. jfitch@bcm.tmc.edu
authors.forename: J C
authors.initials: JC
authors.lastname: Fitch
authors.forename: S
authors.initials: S
authors.lastname: Rollins
authors.forename: L
authors.initials: L
authors.lastname: Matis
authors.forename: B
authors.initials: B
authors.lastname: Alford
authors.forename: S
authors.initials: S
authors.lastname: Aranki
authors.forename: C D
authors.initials: CD
authors.lastname: Collard
authors.forename: M
authors.initials: M
authors.lastname: Dewar
authors.forename: J
authors.initials: J
authors.lastname: Elefteriades
authors.forename: R
authors.initials: R
authors.lastname: Hines
authors.forename: G
authors.initials: G
authors.lastname: Kopf
authors.forename: P
authors.initials: P
authors.lastname: Kraker
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: R
authors.initials: R
authors.lastname: O'Hara
authors.forename: C
authors.initials: C
authors.lastname: Rinder
authors.forename: H
authors.initials: H
authors.lastname: Rinder
authors.forename: R
authors.initials: R
authors.lastname: Shaw
authors.forename: B
authors.initials: B
authors.lastname: Smith
authors.forename: G
authors.initials: G
authors.lastname: Stahl
authors.forename: S K
authors.initials: SK
authors.lastname: Shernan
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D016063:Blood Loss, Surgical; D002315:Cardiopulmonary Bypass; D003072:Cognition Disorders / Q000453:epidemiology / Q000517:prevention & control; D003167:Complement Activation; D003182:Complement C5 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000276:immunology*; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000601:surgery*; D003402:Creatine Kinase / Q000097:blood; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D007527:Isoenzymes; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*; D011183:Postoperative Complications / Q000453:epidemiology / Q000517:prevention & control; D011446:Prospective Studies; D011581:Psychological Tests; D057127:Single-Chain Antibodies
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003182:Complement C5; D015938:Complement Membrane Attack Complex; D007527:Isoenzymes; D057127:Single-Chain Antibodies; C402724:pexelizumab; D003402:Creatine Kinase