BACKGROUND AND PURPOSE: Enlimomab, a murine monoclonal anti-human intercellular 
adhesion molecule (ICAM)-1 antibody, had a negative outcome in a multicenter 
acute-stroke trial. We did a bedside-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 
hypertensive rats (SHR), we administered murine anti-rat ICAM-1 antibody (1A29), 
subclass-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 myeloperoxidase 
activity, neutrophil CD11b expression, and microvascular E-selectin, P-selectin, 
and ICAM-1 expression were examined 48 hours after surgery. Complement 
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-mouse 
antibodies. Although 1A29 inhibited neutrophil trafficking shown by reduction in 
brain myeloperoxidase activity, circulating neutrophils were activated and 
displayed CD11b upregulation. Complement was activated in 1A29-sensitized Wistar 
rats and 1A29-treated SHR. E-selectin (SHR), endothelial P-selectin (Wistar and 
SHR), and ICAM-1 (SHR) were upregulated in animals treated with 1A29.
CONCLUSIONS: Administration to rats of a murine antibody preparation against 
ICAM-1, 1A29, elicits the production of host antibodies against the protein, 
activation of circulating neutrophils, complement activation, and sustained 
microvascular activation. These observations provide several possible mechanisms 
for central nervous system-related clinical deterioration that occurred when 
Enlimomab was given in acute ischemic stroke.