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

Research output: Contribution to journalArticle

Abstract

Although inhibiting interaction of β2 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.

Original languageEnglish (US)
Pages (from-to)907-914
Number of pages8
JournalCirculation research
Volume91
Issue number10
DOIs
StatePublished - Nov 15 2002
Externally publishedYes

Keywords

  • Brain ischemia
  • Cell adhesion molecules
  • E-selectin
  • P-selectin
  • Papio

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Mocco, J., Choudhri, T., Huang, J., Harfeldt, E., Efros, L., Klingbeil, C., Vexler, V., Hall, W., Zhang, Y., Mack, W., Popilskis, S., Pinsky, D. J., & Connolly, E. S. (2002). HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circulation research, 91(10), 907-914. https://doi.org/10.1161/01.RES.0000042063.15901.20