doi: 10.1161/hs3211.098535
(Stroke. 2001;32:2665.)
© 2001 American Heart Association, Inc.
Original Contributions |
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
From the Stroke Branch (K.F., H.T., S.A., R.M.M., Y.C., C.A.R., T.J.D., J.M.H.), National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md; Resuscitative Medicine Department (R.M.M.), National Medical Research Center, Silver Spring, Md; Biomedical Instrumentation Center (K.M.W.), Flow Cytometry Facility, Uniformed Services University of the Health Sciences, Bethesda, Md; the Department of Immunology (R.R.), Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Conn; and the Department of Immunology (T.E.H.) and the Department of Molecular and Experimental Medicine (G.J.d.Z.), The Scripps Research Institute, La Jolla, Calif.
Reprint requests to John M. Hallenbeck, MD, Chief, Stroke Branch, NINDS, NIH, 36 Convent Dr, MSC 4128, Bldg 36, Room 4A03, Bethesda, MD 20892-4128. E-mail Hallenbj{at}ninds.nih.gov
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.
Key Words: antibodies • cell adhesion molecules • cerebral ischemia • clinical trials • leukocytes • rats
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