Noninvasive Imaging of Oxidized Low-density Lipoprotein in Atherosclerotic Plaques with Tagged Oxidation-specific Antibodies

The lipid component of vulnerable atherosclerotic lesions strongly determines the propensity for plaque rupture. Oxidized low-density lipoprotein (OxLDL) is a major component of the plaque lipid pool and contributes significantly to the inflammatory milieu. Because oxidation-specific antibodies (Ox-AB) have been shown to selectively immunostain human atherosclerotic lesions, we hypothesized that tagged Ox-AB may be useful for noninvasive imaging of atherosclerosis. Indeed, intravenously injected (125)I-MDA2, a prototype murine monoclonal Ox-AB, has strong selectivity for and accurately identifies lipid-rich atherosclerotic lesions in their entirety. Plaque uptake of (125)I-MDA2 strongly correlates with extent of atherosclerosis, measured by percentage of surface area and aortic weight, and thus provides an accurate quantitative measure of atherosclerotic burden. Dietary regression studies in mice have shown that (125)I-MDA2 uptake is more sensitive to "regression," not measured by physical dimensions but by depletion of OxLDL, suggesting a novel mechanism of plaque stabilization. In vivo gamma-camera scintigraphy with (99m)Tc-MDA2 revealed that imaging of lipid and oxidation-rich atherosclerotic lesions is feasible with this technique. We have developed IK17, the first human Ox-AB, which recognizes a unique oxidation-specific epitope, and may have significant advantages over murine antibodies. Ox-AB may be tagged with appropriate labels for use in nuclear, magnetic resonance, or ultrasound imaging. Potential applications include early diagnosis of lipid-rich atherosclerotic lesions, screening, and serial follow-up of high-risk individuals, identifying vulnerable plaques, and evaluating novel drug therapies on progression and regression of atherosclerosis.