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.

Abstract

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.

• Authors: K Furuya, H Takeda, S Azhar, R M McCarron, Y Chen, C A Ruetzler, K M Wolcott, T J DeGraba, R Rothlein, T E Hugli, G J del Zoppo, J M Hallenbeck
• Journal: Stroke (Stroke) Vol. 32 Issue 11 Pg. 2665-74 (Nov 2001) ISSN: 1524-4628 [Electronic] United States
• PMID: 11692032 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Isoantibodies
• Selectins
• complement C3a, des-Arg-(77)-
• Intercellular Adhesion Molecule-1
• Complement C3a
• Peroxidase

Topics

• Animals
• Antibodies, Monoclonal (adverse effects, immunology, therapeutic use)
• Body Weight
• Brain (enzymology)
• Brain Infarction (etiology, immunology, pathology)
• Brain Ischemia (etiology, immunology, pathology)
• Cerebrovascular Circulation
• Clinical Trials as Topic
• Complement C3a (analogs & derivatives, analysis)
• Flow Cytometry
• Humans
• Immunohistochemistry
• Intercellular Adhesion Molecule-1 (immunology)
• Isoantibodies (adverse effects, immunology, therapeutic use)
• Laser-Doppler Flowmetry
• Leukocyte Count
• Mice
• Peroxidase (metabolism)
• Rats
• Rats, Inbred SHR
• Rats, Wistar
• Selectins (analysis, immunology)
• Stroke (therapy)