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(Circulation Research. 2002;91:907.)
© 2002 American Heart Association, Inc.

Molecular Medicine

HuEP5C7 as a Humanized Monoclonal Anti-E/P-Selectin Neurovascular Protective Strategy in a Blinded Placebo-Controlled Trial of Nonhuman Primate Stroke

J. Mocco^*, Tanvir Choudhri^*, Judy Huang, Elisabeth Harfeldt, Lyubov Efros, Corine Klingbeil, Vladimir Vexler, William Hall, Yuan Zhang, William Mack, Sulli Popilskis, David J. Pinsky, E. Sander Connolly, Jr

From the Departments of Neurological Surgery (J.M., T.C., J.H., Y.Z., W.M., E.S.C.) and Medicine (D.J.P.), and the Institute of Comparative Medicine (S.P.), Columbia University College of Physicians and Surgeons, New York, NY; Protein Design Labs, Inc (E.H., L.E., C.K., V.V.), Fremont, Calif; and Pathology Associates (W.H.), A Charles River Company, Frederick, Md.

Correspondence to E. Sander Connolly, Jr, MD, Columbia University College of Physicians & Surgeons, 710 West 168th St, Box 72, New York, NY 10032. E-mail esc5{at}columbia.edu

Although inhibiting interaction of ß₂ integrins with cognate immunoglobulin class adhesion receptor ligands is an effective neuroprotective strategy in small mammal models of stroke, the strategy has failed in human trials. A completely different antiadhesion receptor strategy was therefore rigorously tested in a model that may more closely approximate human reperfused stroke. Early leukoadhesive events in postischemic cerebral microvessels are mediated by upregulated selectin-class adhesion receptors on endothelial cells. Therefore, a blocking antibody prepared against common P- and E-selectin epitopes was humanized to suppress complement activation and tested in a reperfused hemispheric stroke model in Papio anubis (baboon). Histological examination of postischemic cerebral microvessels revealed a strong upregulation of E-and P-selectin expression. Placebo-blinded administration of the humanized anti-human E- and P-selectin monoclonal antibody (HuEP5C7, 20 mg/kg IV, n=9; placebo, n=9) immediately after the onset of 1 hour of temporary ischemia resulted in trends showing reduced polymorphonuclear leukocyte (PMN) infiltration into ischemic cortex, reduced infarct volumes (by 41%), improved neurological score (by 35%), and improved ability to self-care (by 39%). Importantly, there was no evidence of systemic complement activation, immune suppression, or pathological coagulopathy associated with this therapy. These data suggest that a humanized anti-E/P-selectin antibody approach is safe and may be effective as a clinical treatment for human stroke.

Key Words: cell adhesion molecules • E-selectin • P-selectin • Papio • brain ischemia

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