HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke.
Although inhibiting interaction of beta(2) 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.
Mocco
J
J
Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Choudhri
Tanvir
T
Huang
Judy
J
Harfeldt
Elisabeth
E
Efros
Lyubov
L
Klingbeil
Corine
C
Vexler
Vladimir
V
Hall
William
W
Zhang
Yuan
Y
Mack
William
W
Popilskis
Sulli
S
Pinsky
David J
DJ
Connolly
E Sander
ES
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use*; D000918:Antibody Specificity / Q000235:genetics / Q000276:immunology; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D003165:Complement System Proteins / Q000032:analysis / Q000187:drug effects; D004195:Disease Models, Animal; D019040:E-Selectin / Q000097:blood / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000276:immunology; D007958:Leukocyte Count; D018810:Magnetic Resonance Angiography; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D019007:P-Selectin / Q000097:blood / Q000276:immunology*; D010215:Papio; D011446:Prospective Studies; D016037:Single-Blind Method; D013045:Species Specificity; D020521:Stroke / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D019040:E-Selectin; D018696:Neuroprotective Agents; D019007:P-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D003165:Complement System Proteins