TY - JOUR
T1 - PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis
AU - Senders, Max L.
AU - Que, Xuchu
AU - Cho, Young Seok
AU - Yeang, Calvin
AU - Groenen, Hannah
AU - Fay, Francois
AU - Calcagno, Claudia
AU - Meerwaldt, Anu E.
AU - Green, Simone
AU - Miu, Phuong
AU - Lobatto, Mark E.
AU - Reiner, Thomas
AU - Fayad, Zahi A.
AU - Witztum, Joseph L.
AU - Mulder, Willem J. M.
AU - Pérez-Medina, Carlos
AU - Tsimikas, Sotirios
PY - 2018
Y1 - 2018
N2 - BACKGROUND Oxidation-specific epitopes (OSEs) are proinflammatory, and elevated levels in plasma predict cardiovascular events. OBJECTIVES The purpose of this study was to develop novel positron emission tomography (PET) probes to noninvasively image OSE-rich lesions. METHODS An antigen-binding fragment (Fab) antibody library was constructed from human fetal cord blood. After multiple rounds of screening against malondialdehyde-acetaldehyde (MAA) epitopes, the Fab LA25 containing minimal nontemplated insertions in the CDR3 region was identified and characterized. In mice, pharmacokinetics, biodistribution, and plaque specificity studies were performed with Zirconium-89 (Zr-89)-labeled LA25. In rabbits, Zr-89-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. F-18-fluorodeoxyglucose PET and dynamic contrast-enhanced MR imaging were used to evaluate vessel wall inflammation and plaque neovascularization, respectively. Extensive ex vivo validation was carried out through a combination of gamma counting, near infrared fluorescence, autoradiography, immunohistochemistry, and immunofluorescence. RESULTS LA25 bound specifically to MAA epitopes in advanced and ruptured human atherosclerotic plaques with accompanying thrombi and in debris from distal protection devices. PET/MR imaging 24 h after injection of Zr-89-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. F-18-fluorodeoxyglucose PET, dynamic contrastenhanced MR imaging, and near-infrared fluorescence signals were also significantly higher in atherosclerotic rabbit aortas compared with control aortas. Enhanced liver uptake was also noted in atherosclerotic animals, confirmed by the presence of MAA epitopes by immunostaining. CONCLUSIONS Zr-89-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions. (c) 2018 by the American College of Cardiology Foundation
AB - BACKGROUND Oxidation-specific epitopes (OSEs) are proinflammatory, and elevated levels in plasma predict cardiovascular events. OBJECTIVES The purpose of this study was to develop novel positron emission tomography (PET) probes to noninvasively image OSE-rich lesions. METHODS An antigen-binding fragment (Fab) antibody library was constructed from human fetal cord blood. After multiple rounds of screening against malondialdehyde-acetaldehyde (MAA) epitopes, the Fab LA25 containing minimal nontemplated insertions in the CDR3 region was identified and characterized. In mice, pharmacokinetics, biodistribution, and plaque specificity studies were performed with Zirconium-89 (Zr-89)-labeled LA25. In rabbits, Zr-89-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. F-18-fluorodeoxyglucose PET and dynamic contrast-enhanced MR imaging were used to evaluate vessel wall inflammation and plaque neovascularization, respectively. Extensive ex vivo validation was carried out through a combination of gamma counting, near infrared fluorescence, autoradiography, immunohistochemistry, and immunofluorescence. RESULTS LA25 bound specifically to MAA epitopes in advanced and ruptured human atherosclerotic plaques with accompanying thrombi and in debris from distal protection devices. PET/MR imaging 24 h after injection of Zr-89-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. F-18-fluorodeoxyglucose PET, dynamic contrastenhanced MR imaging, and near-infrared fluorescence signals were also significantly higher in atherosclerotic rabbit aortas compared with control aortas. Enhanced liver uptake was also noted in atherosclerotic animals, confirmed by the presence of MAA epitopes by immunostaining. CONCLUSIONS Zr-89-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions. (c) 2018 by the American College of Cardiology Foundation
U2 - https://doi.org/10.1016/j.jacc.2017.11.036
DO - https://doi.org/10.1016/j.jacc.2017.11.036
M3 - Article
C2 - 29348025
SN - 0735-1097
VL - 71
SP - 321
EP - 335
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 3
ER -