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(Circulation Research. 2004;95:1225.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Molecular Imaging of Atherosclerotic Plaques Using a Human Antibody Against the Extra-Domain B of Fibronectin

Christian M. Matter^*, Pia K. Schuler^*, Patrizia Alessi, Patricia Meier, Romeo Ricci, Dongming Zhang, Cornelia Halin, Patrizia Castellani, Luciano Zardi, Christoph K. Hofer, Matteo Montani, Dario Neri, Thomas F. Lüscher

From the Cardiovascular Research, Institute of Physiology (C.M.M., P.K.S., P.M., R.R., D.Z., T.F.L.), University of Zurich and Cardiovascular Center, Zurich University Hospital, Switzerland; Department of Chemistry and Applied Biosciences (P.A., C.H., D.N.), Swiss Federal Institute of Technology, Zurich, Switzerland; Laboratory of Cell Biology (P.C.), Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Unit of Innovative Therapies (L.Z.), Department of Experimental and Clinical Immunology, Istituto Giannina Gaslini, Genoa, Italy; Institute of Anaesthesiology (C.K.H.), Triemli City Hospital, Zurich, Switzerland; and the Institute of Pathology (M.M.), Zurich University Hospital, Switzerland.

Correspondence to Dario Neri, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Wolfgang-Pauli Strasse 10, CH-8093 Zurich, Switzerland. E-mail neri{at}pharma.ethz.ch

Current imaging modalities of human atherosclerosis, such as angiography, ultrasound, and computed tomography, visualize plaque morphology. However, methods that provide insight into plaque biology using molecular tools are still insufficient. The extra-domain B (ED-B) is inserted into the fibronectin molecule by alternative splicing during angiogenesis and tissue remodeling but is virtually undetectable in normal adult tissues. Angiogenesis and tissue repair are also hallmarks of advanced plaques. For imaging atherosclerotic plaques, the human antibody L19 (specific against ED-B) and a negative control antibody were labeled with radioiodine or infrared fluorophores and injected intravenously into atherosclerotic apolipoprotein E–null (ApoE^–/–) or normal wild-type mice. Aortas isolated 4 hours, 24 hours, and 3 days after injection exhibited a selective and stable uptake of L19 when using radiographic or fluorescent imaging. L19 binding was confined to the plaques as assessed by fat staining. Comparisons between fat staining and autoradiographies 24 hours after ¹²⁵I-labeled L19 revealed a significant correlation (r=0.89; P<0.0001). Minimal antibody uptake was observed in normal vessels from wild-type mice receiving the L19 antibody and in atherosclerotic vessels from ApoE^–/– mice receiving the negative control antibody. Immunohistochemical studies revealed increased expression of ED-B not only in murine but also in human plaques, in which it was found predominantly around vasa vasorum and plaque matrix. In summary, we demonstrate selective targeting of atheromas in mice using the human antibody to the ED-B domain of fibronectin. Thus, our findings may set the stage for antibody-based molecular imaging of atherosclerotic plaques in the intact organism.

Key Words: vascular targeting • angiogenesis • apolipoprotein E–null mice • near infrared

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