HUMANIZED MONOCLONAL-ANTIBODY DREG-200 DIRECTED AGAINST L-SELECTIN PROTECTS IN FELINE MYOCARDIAL REPERFUSION INJURY

Polymorphonuclear leukocytes (i.e. neutrophils) significantly mediate damage in myocardial ischemia followed by reperfusion. In the present study, the cardioprotective effects of a humanized form of a monoclona l antibody directed against L-selectin designated monoclonal antibody (mAb) HuDREG-200 were examined in a feline model of 90-min myocardial ischemia followed by 270 min of reperfusion. In preliminary studies, f low cytometric analysis indicated that HuDREG-200 binds to feline neut rophils. In vitro administration of mAb HuDREG-200 significantly inhib ited (P < .01) adherence of unstimulated neutrophils to ischemic-reper fused coronary endothelium in a concentration-dependent manner. Humani zed DREG-200 (2 mg/kg) administered 10 min before reperfusion signific antly attenuated myocardial necrosis compared to an isotype-matched hu manized control mAb (HuABL364) which does not bind to L-selectin (14 /- 3 vs. 29 +/- 3% necrosis/area-at-risk, P < .01), representing a 52% reduction in myocardial necrosis. This myocardial preservation also w as related to reduced creatine kinase release and improved recovery of cardiac contractility (i.e. left ventricular dP/dt(max). Moreover, en dothelial function, as assessed by relaxation to acetylcholine, also w as significantly preserved in ischemic-reperfused coronary arteries is olated from cats treated with mAb HuDREG-200 compared to mAb HuABL364 (68 +/- 6 vs. 18 +/- 5, P < .01). Thus, a humanized anti-L-selectin mA b appears to be an effective means of preserving the ischemic myocardi um from reperfusion injury and of preserving myocardial contractile fu nction, at least during the early reperfusion period.