Max L Senders1, Xuchu Que2, Young Seok Cho3, Calvin Yeang4, Hannah Groenen5, Francois Fay6, Claudia Calcagno5, Anu E Meerwaldt5, Simone Green4, Phuong Miu4, Mark E Lobatto7, Thomas Reiner8, Zahi A Fayad5, Joseph L Witztum2, Willem J M Mulder1, Carlos Pérez-Medina9, Sotirios Tsimikas10. 1. Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands. 2. Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, California. 3. Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea; Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Department of Medicine, University of California San Diego, La Jolla, California. 4. Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Department of Medicine, University of California San Diego, La Jolla, California. 5. Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 6. Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Chemistry and Pharmaceutical Science, York College of The City University of New York, New York, New York. 7. Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands. 8. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Radiology, Weill Cornell Medical College, New York, New York. 9. Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: carlos.perez-medina@mountsinai.org. 10. Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Department of Medicine, University of California San Diego, La Jolla, California. Electronic address: stsimikas@ucsd.edu.
Abstract
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 (89Zr)-labeled LA25. In rabbits, 89Zr-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. 18F-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 89Zr-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. 18F-fluorodeoxyglucose PET, dynamic contrast-enhanced 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: 89Zr-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions.
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 FabLA25 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 (89Zr)-labeled LA25. In rabbits, 89Zr-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. 18F-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 humanatherosclerotic plaques with accompanying thrombi and in debris from distal protection devices. PET/MR imaging 24 h after injection of 89Zr-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. 18F-fluorodeoxyglucose PET, dynamic contrast-enhanced 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: 89Zr-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions.
Authors: M K Chang; C Bergmark; A Laurila; S Hörkkö; K H Han; P Friedman; E A Dennis; J L Witztum Journal: Proc Natl Acad Sci U S A Date: 1999-05-25 Impact factor: 11.205
Authors: Ayelet Gonen; Lotte F Hansen; William W Turner; Erica N Montano; Xuchu Que; Apaїs Rafia; Meng-Yun Chou; Philipp Wiesner; Dimitrios Tsiantoulas; Maripat Corr; Michael S VanNieuwenhze; Sotirios Tsimikas; Christoph J Binder; Joseph L Witztum; Karsten Hartvigsen Journal: J Lipid Res Date: 2014-08-20 Impact factor: 5.922
Authors: Michael J Duryee; Lynell W Klassen; Courtney S Schaffert; Dean J Tuma; Carlos D Hunter; Robert P Garvin; Daniel R Anderson; Geoffrey M Thiele Journal: Free Radic Biol Med Date: 2010-08-06 Impact factor: 7.376
Authors: Veerle Bieghs; Sofie M A Walenbergh; Tim Hendrikx; Patrick J van Gorp; Fons Verheyen; Steven W Olde Damink; Ad A Masclee; Ger H Koek; Marten H Hofker; Christoph J Binder; Ronit Shiri-Sverdlov Journal: Liver Int Date: 2013-04-25 Impact factor: 5.828
Authors: Ramzi Y Khamis; Kevin J Woollard; Gareth D Hyde; Joseph J Boyle; Colin Bicknell; Shang-Hung Chang; Talat H Malik; Tetsuya Hara; Adam Mauskapf; David W Granger; Jason L Johnson; Vasilis Ntziachristos; Paul M Matthews; Farouc A Jaffer; Dorian O Haskard Journal: Sci Rep Date: 2016-02-25 Impact factor: 4.379