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Human Antibody Against C Domain of Tenascin-C Visualizes Murine Atherosclerotic Plaques Ex Vivo

¹ Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland; ² Cardiology, CardioVascular Center, Zurich University Hospital, Zurich, Switzerland; ³ Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; ⁴ Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Zurich, Switzerland; and ⁵ Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland

Correspondence: For correspondence contact: Christian M. Matter, MD, Cardiovascular Research, Institute of Physiology, Zurich University, and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. E-mail: cmatter{at}physiol.unizh.ch

Targeting proteins that are overexpressed in atherosclerotic plaques may open novel diagnostic applications. The C domain of tenascin-C is absent from normal adult tissues but can be inserted during tumor progression or tissue repair into the molecule by alternative splicing. We tested the ability of the human antibody G11, specific to this antigen, to reveal murine atherosclerotic plaques ex vivo. The antibody directed against the extra domain B of fibronectin (L19) was used as a reference. Methods: We intravenously injected ¹²⁵I-labeled G11 or L19 antibodies into apolipoprotein E-deficient (ApoE^–/–) mice and harvested the aortae 4 or 24 h later. En face analyses of distal aortae and longitudinal sections of the aortic arch were performed to compare antibody uptake using autoradiography with plaque staining using oil red O. Plaque macrophages were detected by immunohistochemistry (anti-CD68 staining). Biodistribution of injected antibodies was investigated in aortae and blood at 4 and 24 h. Results: En face analyses revealed a significant correlation between radiolabeled G11 and fat-stained areas, increasing from 4 to 24 h, with a correlation coefficient of 0.92 (P < 0.0001) and an average signal-to-noise ratio of 104:1 at 24 h. Plaque imaging using L19 showed similar results (r = 0.86; P < 0.0001; signal-to-noise ratio, 72:1 at 24 h). Uptake of radiolabeled antibodies in histologic sections colocalized with fat staining and activated macrophages in aortic plaques. Biodistribution analyses confirmed specific accumulation in aortic plaques as well as rapid blood pool clearance of the antibodies 24 h after injection. Immunofluorescence analyses revealed increased expression of tenascin and fibronectin isoforms in macrophage-rich plaques. Conclusion: The antibody G11, specific to the C domain of tenascin-C, visualizes murine atherosclerotic plaques ex vivo. In conjunction with the increased expression of the C domain of tenascin-C in macrophage-rich plaques, the colocalization of G11 uptake with activated macrophages, and the favorable target-to-blood ratio at 24 h, this antibody may be useful for molecular imaging of advanced atherosclerotic plaques in the intact organism.

Key Words: atherosclerosis • autoradiography • molecular imaging • cardiology (basic/technical) • correlative imaging

^* Contributed equally to this work.

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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