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Humanized monoclonal antibody DREG-200 directed against I-selectin protects in feline myocardial reperfusion injury.

Abstract
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 monoclonal 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, flow cytometric analysis indicated that HuDREG-200 binds to feline neutrophils. In vitro administration of mAb HuDREG-200 significantly inhibited (P < .01) adherence of unstimulated neutrophils to ischemic-reperfused coronary endothelium in a concentration-dependent manner. Humanized DREG-200 (2 mg/kg) administered 10 min before reperfusion significantly attenuated myocardial necrosis compared to an isotype-matched humanized 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 was related to reduced creatine kinase release and improved recovery of cardiac contractility (i.e. left ventricular dP/dtmax). Moreover, endothelial function, as assessed by relaxation to acetylcholine, also was significantly preserved in ischemic-reperfused coronary arteries isolated from cats treated with mAb HuDREG-200 compared to mAb HuABL364 (68 +/- 6 vs. 18 +/- 5, P < .01). Thus, a humanized anti-L-selectin mAb appears to be an effective means of preserving the ischemic myocardium from reperfusion injury and of preserving myocardial contractile function, at least during the early reperfusion period.
AuthorsM Buerke, A S Weyrich, T Murohara, C Queen, C K Klingbeil, M S Co, A M Lefer
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 271 Issue 1 Pg. 134-42 (Oct 1994) ISSN: 0022-3565 [Print] United States
PMID7525923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antibodies, Monoclonal
  • Cell Adhesion Molecules
  • L-Selectin
Topics
  • Animals
  • Antibodies, Monoclonal (immunology, therapeutic use)
  • Cats
  • Cell Adhesion
  • Cell Adhesion Molecules (immunology, physiology)
  • Cross Reactions
  • Endothelium, Vascular (physiology)
  • Hemodynamics
  • Humans
  • L-Selectin
  • Leukocyte Count
  • Male
  • Myocardial Reperfusion Injury (prevention & control)
  • Neutrophils (physiology)

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