HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke
| Autor: | Judy Huang, Lyubov Efros, J. Mocco, Sulli Popilskis, Corine Klingbeil, William C. Hall, William J. Mack, E. Sander Connolly, Tanvir F. Choudhri, Yuan Zhang, Vladimir Vexler, David J. Pinsky, Elisabeth Harfeldt |
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| Rok vydání: | 2002 |
| Předmět: |
Physiology
Vascular Cell Adhesion Molecule-1 Humanized antibody Neuroprotection Brain ischemia Leukocyte Count Species Specificity Antibody Specificity E-selectin Blocking antibody Medicine Animals Humans Single-Blind Method Prospective Studies Stroke biology business.industry Antibodies Monoclonal Brain Complement System Proteins medicine.disease Intercellular Adhesion Molecule-1 Disease Models Animal P-Selectin Neuroprotective Agents Treatment Outcome Neutrophil Infiltration Immunology Monoclonal biology.protein Antibody Cardiology and Cardiovascular Medicine business E-Selectin Magnetic Resonance Angiography Papio |
| Zdroj: | Circulation research. 91(10) |
| ISSN: | 1524-4571 |
| Popis: | Although inhibiting interaction of β2integrins 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 Papioanubis(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. |
| Databáze: | OpenAIRE |
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