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. 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 (PϽ0.05) in patients who received 1 and 2 mg/kg. There was a 40% reduction in myocardial injury (creatine kinase-MB release, Pϭ0.05) in patients who received 2 mg/kg. Sequential Mini-Mental State Examinations (MMSE) demonstrated an 80% reduction in new cognitive deficits (PϽ0.05) in patients treated with 2 mg/kg. Finally, there was a 1-U reduction in postoperative blood loss (PϽ0.05) 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. (Circulation. 1999;100:2499-2506.)

Pathophysiology of renal disease associated with liver disorders: Implications for liver transplantation. Part I

“…[177][178][179][180][181] In addition, renal damage has been limited by the administration of anti-C5 during cardiac bypass. 182 Furthermore, complement inhibition also may limit damage caused by proteinuria. For example, in the rat model of nephrotic proteinuria-induced renal fibrosis, fibrosis is reduced in animals deficient in C6 that cannot generate the C5b-9 membrane attack complex, as well as in animals treated to deplete or bind complement components (by soluble complement receptor type 1).…”

Membrane Attack Complex Contributes to Destruction of Vascular Integrity in Acute Lung Allograft Rejection

“…Pulmonary edema results from systemic activation of complement with cobra venom in experimental models or in clinical procedures such as cardiopulmonary bypass (23,56). This injury has been attributed to biological effects of C5a and MAC.…”

A Humanized Single-Chain Variable Fragment Antibody Against Beta3 Integrin in Escherichia coli

“…2B). The scFv form has additional unparalleled advantages for clinical utility, (7)(8)(9) with their recombinant feature allowing for further genetic engineering such as affinity maturation and construction of fusion molecules for high clot-target avidity. (10)(11)(12)(13) Binding activity of A11 to platelet integrin GPIIIa49-66…”