Molecular imaging of atherosclerotic plaques using a human antibody against the extra-domain B of fibronectin.
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.
Matter
Christian M
CM
Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiovascular Center, Zurich University Hospital, Switzerland.
Schuler
Pia K
PK
Alessi
Patrizia
P
Meier
Patricia
P
Ricci
Romeo
R
Zhang
Dongming
D
Halin
Cornelia
C
Castellani
Patrizia
P
Zardi
Luciano
L
Hofer
Christoph K
CK
Montani
Matteo
M
Neri
Dario
D
Lüscher
Thomas F
TF
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000915:Antibody Affinity; D001011:Aorta / Q000737:chemistry / Q000648:ultrastructure; D001012:Aorta, Abdominal / Q000737:chemistry / Q000648:ultrastructure; D001018:Aortic Diseases / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002232:Carbocyanines; D003331:Coronary Vessels / Q000737:chemistry / Q000648:ultrastructure; D004036:Diet, Atherogenic; D005353:Fibronectins / Q000032:analysis* / Q000276:immunology; D005456:Fluorescent Dyes / Q000032:analysis; D006801:Humans; D007083:Iliac Artery / Q000737:chemistry / Q000648:ultrastructure; D008297:Male; D008323:Mammary Arteries / Q000737:chemistry / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D017434:Protein Structure, Tertiary; D016719:Radioimmunodetection; D011994:Recombinant Proteins / Q000276:immunology; D019265:Spectroscopy, Near-Infrared; D014651:Vasa Vasorum / Q000737:chemistry / Q000648:ultrastructure
D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D002232:Carbocyanines; C067625:FN1 protein, human; D005353:Fibronectins; D005456:Fluorescent Dyes; D011994:Recombinant Proteins; C501744:indotricarbocyanine