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NOVEL ANTI-FACTOR D MONOCLONAL ANTIBODY INHIBITS COMPLEMENT AND LEUKOCYTE ACTIVATION IN A BABOON MODEL OF CARDIOPULMONARY BYPASS A. Ündar, H.C. Eichstaedt, F.J.Clubb, Jr, M. Fung, M. Lu, J.E. Bigley, B. Deady, A. Porter, W.K. Vaughn, C.D. Fraser, Jr. Texas Children’s Hospital, Baylor College of Medicine, Texas Heart Institute, Tanox, Inc., Houston, TX. Purpose: Patients undergoing cardiopulmonary bypass (CPB) frequently manifest a generalized systemic inflammation that is associated with complement and leukocyte activation. The objective of this study was to investigate the effects of inhibition of the alternative complement pathway on systemic inflammation and tissue injury, using a novel monoclonal antibody (Mab), anti-factor D Mab 166- 32, during hypothermic CPB in baboons. Methods: Fourteen baboons (mean weight, 15 kg) underwent hypothermic CPB. Seven of them were treated with a single injection of anti-factor D Mab 166-32 (5 mg/kg) and the other seven animals were given saline as control. After initiation of CPB, all animals were subjected to 20 minutes of core cooling (rectal temperature, 27oC), followed by 60 minutes of aortic cross-clamping, 25 minutes of rewarming, and 30 minutes of normothermic CPB. Blood samples were collected before CPB, during CPB, and 1, 2, 3, and 6 hours after CPB. Assays were performed to measure neutrophil and monocyte activation using flow cytometry for CD11b expression, ELISA for complement activation (C3a, sC5b-9 and Bb) and IL-6 production, and myocardial injury for CK, CK-MB, and LDH levels.Results: The following results were documented after 6 hours of CPB (mean±SD). Assay Control Mab 166-32 p value Bb(ng/ml) 547±155 147±38 0.0001 C3a(µg/ml) 24±15 10±5 0.0001 sC5b-9(ng/ml) 167±53 82±51 0.0001 IL-6(pg/ml) 104±54 71±27 0.0002 CD11b(neutrophils) 8.9±4.5 4.8±1.6 0.0001 CD11b(monocytes) 5.7±3 3.6±1 0.001 CK-MB(IU/L) 336±145 204±73 0.03 CK and LDH levels were also significantly lower in the antibody group. Conclusions: The alternative complement pathway plays a major role in systemic inflammation during CPB. Inhibition of complement activation via the alternative pathway by anti-factor D Mab 166-32 significantly reduces leukocyte activation, and myocardial injury in our baboon model.
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