NOVEL ANTI FACTOR MONOCLONAL ANTIBODY INHIBITS COMPLEMENT AND

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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.