Examination of several potential mechanisms for the negative outcome in a clinical stroke trial of enlimomab, a murine anti-human intercellular adhesion molecule-1 antibody - A bedside-to-bench study

Background and Purpose-Enlimomab, a murine monoclonal anti-human intercellu lar adhesion molecule (ICAM)-1 antibody, had a negative outcome in a multic enter acute-stroke trial. We did a beds ide-to-bench study in standardized rat stroke models to explore mechanisms for these untoward results. Methods-After focal brain ischemia in Wistar rats and spontaneously hyperte nsive rats (SHR), we administered murine anti-rat ICAM-1 antibody (1A29), s ubclass-matched murine immunoglobulin (IgG1), or vehicle intravenously. To examine whether rat anti-mouse antibodies were generated against the mouse protein and whether these were deleterious, we sensitized Wistar rats with 1A29 or vehicle 7 days before surgery. Infarct volume, tissue myeloperoxida se activity, neutrophil CD11b expression, and microvascular E-selectin, P-s electin, and ICAM-1 expression were examined 48 hours after surgery. Comple ment activation was serially assessed for 2 hours after a single injection of either 1A29 or vehicle. Results- 1A29 treatment did not significantly reduce infarct size in either strain. 1A29 sensitization augmented infarct size and generated rat anti-m ouse antibodies. Although 1A29 inhibited neutrophil trafficking shown by re duction in brain myeloperoxidase activity, circulating neutrophils were act ivated and displayed CD11b upregulation. Complement was activated in 1A29-s ensitized Wistar rats and 1A29-treated SHR. E-selectin (SHR), endothelial P -selectin (Wistar and SHR), and ICAM-1 (SHR) were upregulated in animals tr eated with 1A29. Conclusions-Administration to rats of a murine antibody preparation against ICAM-1, 1A29, elicits the production of host antibodies against the protei n, activation of circulating neutrophils, complement activation, and sustai ned microvascular activation. These observations provide several possible m echanisms for central nervous system-related clinical deterioration that oc curred when Enlimomab was given in acute ischemic stroke.