PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis

Max L Senders; Xuchu Que; Young Seok Cho; Calvin Yeang; Hannah Groenen; Francois Fay; Claudia Calcagno; Anu E Meerwaldt; Simone Green; Phuong Miu; Mark E Lobatto; Thomas Reiner; Zahi A Fayad; Joseph L Witztum; Willem J M Mulder; Carlos Pérez-Medina; Sotirios Tsimikas

doi:10.1016/j.jacc.2017.11.036

PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis

J Am Coll Cardiol. 2018 Jan 23;71(3):321-335. doi: 10.1016/j.jacc.2017.11.036.

Authors

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

Affiliations

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.

Keywords: PET/MR imaging; atherosclerosis; natural antibodies; oxidation-specific epitopes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetaldehyde* / metabolism
Animals
Atherosclerosis / diagnostic imaging*
Atherosclerosis / metabolism
Epitopes / metabolism
Humans
Magnetic Resonance Imaging / methods*
Malondialdehyde* / metabolism
Mice
Mice, Knockout
Positron-Emission Tomography / methods*
Rabbits
Thrombosis / diagnostic imaging*
Thrombosis / metabolism
Tissue Distribution / physiology

Substances

Epitopes
Malondialdehyde
Acetaldehyde

Abstract

Publication types

MeSH terms

Substances

Grants and funding