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Noninvasive imaging of early atherosclerosis

Institution: University of California, San Diego
Investigator(s): Sotirios Tsimikas, M.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6KT-0100 Award: $101,923
Subject Area: Cardiovascular Disease
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
Atherosclerosis is a condition which results in narrowing or obstruction of arteries and results in strokes, heart attacks and death. Approximately one out every two deaths in the United States is caused by this disease. While there are many causes leading to atherosclerosis, high levels of LDL cholesterol and smoking are two of the major factors. High levels of LDL, the so-called “bad cholesterol", enter the artery which leads to atherosclerosis. We now know that when the LDL particles are oxidized, a process in which oxygen is attached to the lipid (fat) parts of the LDL, that the LDL particle becomes even more damaging. Oxidized LDL (Ox-LDL) injures the artery wall and is rapidly taken up by cells in the artery leading to even more cholesterol deposition. Tobacco smoke is known to contain a large number of compounds which are pro-oxidants, and it is believed that these further enhance the oxidation of LDL and in this way may promote atherosclerosis.

Unfortunately, there is no easy and safe method to diagnose atherosclerosis at its early stages. Investigators at UCSD have previously developed monoclonal antibodies that will bind to Ox-LDL. Antibodies are proteins produced by the immune system to help fight disease by recognizing foreign invaders. These investigators have shown that these antibodies bind to aortic tissue. Over the past two years I have developed considerable evidence that these antibodies can be injected into the blood vessels and that they will be taken up specifically by atherosclerotic lesions, but not by normal aorta. If a radioisotope is attached to the antibody, and the antibody is injected intravenously, then it may be possible to detect those portions of the aorta that contain the antibody by external imaging with a nuclear image detector available in every hospital. Alternatively a label detected by magnetic resonance imaging (MRI) might allow detection by MRI analysis, which would not involve the use of radioactivity.

My proposal seeks to develop the optimal ways to accomplish these goals, first by studies in animal models of atherosclerosis and then by translating this research into studies in humans. If this technique can be successfully developed it would allow physicians to image atherosclerosis even at a very early stage and thus allow us to identify individuals who would be at high risk for developing the complications of atherosclerosis and in whom the most vigorous prevention measures should be undertaken. Thus this technique could potentially be an outstanding tool for the physician in determining the extent of atherosclerosis any clinical events occurred and allow the appropriate therapy to be initiated before a heart attack or stroke occurred.

Final Report
Atherosclerosis is a condition which results in narrowing and obstruction of arteries which supply blood to major organs such as the heart muscle, brain, kidneys, and extremities. It accounts for approximately 50% of deaths in the United States and other developed countries. There are many causes leading to atherosclerosis, including smoking, high cholesterol levels, high blood pressure, diabetes and others. Circulating LDL cholesterol enters the artery walls where it undergoes oxidative modification by various processes. This oxidation creates a significantly more atherogenic cholesterol particle leading to progressive narrowing of arteries.

Currently, there is no non-invasive method to diagnose atherosclerosis at its early stages. Over the last 3 years, our research focused on developing a non-invasive technique to detect atherosclerosis that will be safer and less costly than current methods. We have developed several murine monoclonal antibodies that specifically bind to oxidized LDL cholesterol but not normal LDL cholesterol. We have shown that when injected intravenously in animal models, these antibodies accumulate specifically within atherosclerotic lesions but not in normal tissue and that the signal generated by the antibody within the atherosclerotic plaque is proportional to the amount of oxidized LDL and atherosclerotic lesions that is present. As a corollary, circulating autoantibodies to oxidized LDL also correlate with the oxidized LDL detected by the injected monoclonal antibodies. We have shown that 99mTc-labeled MDA2, a prototype oxidation-specific antibody, detects the depletion of oxidized LDL cholesterol may be used to image atherosclerotic lesions noninvasively. Because murine monoclonal antibodies may have potential serious side effects such as allergic/anaphylactic reactions, we have embarked on cloning human antibodies to oxidized LDL and have generated one potential candidate, IK-17. This is an antibody fragment that has all of the advantages of MDA2 but will be the least immunogenic. Potential applications of these techniques may include noninvasive diagnosis of narrowed arteries (i.e. coronary, carotid, renal) due to atherosclerosis, selection of optimal candidates for drug/dietary intervention based on results of imaging, and to follow the natural progression or regression of these lesions.
Publications

Quantitation of atherosclerosis in murine models with a novel and rapid method using in vivo aortic uptake of I-MDA2, and oxidation-specific murine monoclonal antibody
Periodical: Circulation Index Medicus:
Authors: Tsimikas S, Palinski W, Witztum JL ABS
Yr: 1997 Vol: 95 Nbr: Abs: I-490 Pg:

Autoantibodies to oxidized LDL correlate with both arterial accumulation and depletion of oxidized LDL in LDL receptor deficient mice
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Tsimikas S, Palinski W, Witztum JL ART
Yr: 2001 Vol: 21 Nbr: Abs: Pg: 95-100

In vivo uptake of radidolabeled MDA2, an oxidation-specific monoclonal antibody, provides an accurate measure of atherosclerotic lesions rich in oxidized LDL and is highly sensitive to their regression
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Tsimikas S, Shortal B, Witztum JL, Palinski W ART
Yr: 2000 Vol: 20 Nbr: Abs: Pg: 689-697

Radiolabeled MDA2, an oxidation-specific monoclonal antibody identifies native atherosclerotic lesions in vivo
Periodical: Journal of Nuclear Cardiology Index Medicus:
Authors: Tsimikas S, Palinski W, Halpern SA, Yeung DW, Curtiss L, Witztum JL ART
Yr: 1999 Vol: 6 Nbr: Abs: Pg: 41-53

Noninvasive imaging and quantitation of atherosclerosis with radiolabeled oxidation-specific antibodies
Periodical: Atherosclerosis Reviews Index Medicus:
Authors: Tsimias S, Palinski W, Shaw PX, Witztum JL ABS
Yr: 2000 Vol: 151 Nbr: Abs: Pg: 4-5

Biological significance of autoantibodies to oxidative neoepitopes
Periodical: Atherosclerosis Reviews Index Medicus:
Authors: Palinski W, Horkko S, Shaw PX, Tsimikas S, Silverman G, Witztum JL ABS
Yr: 2000 Vol: 151 Nbr: Abs: Pg: 165

In vivo aortic uptake of MDA2 an oxidation-specific monoclonal antibody, detects depletion of oxidized LDL from atherosclerotic lesions
Periodical: Circulation Index Medicus:
Authors: Tsimikas S, Palinski W, Witztum JL ABS
Yr: 1999 Vol: 100 Nbr: I-541 Abs: Pg:

A human Fab antibody cloned from a phage display library binds to epitopes of oxidized LDL and apoptotic cells inhibits their uptake by macrophages and in vivo images atherosclerotic lesions
Periodical: Circulation Index Medicus:
Authors: Shaw PS, Horkko S, Tsimikas S, Chang M-Y, et al ABS
Yr: 1999 Vol: 100 Nbr: I-539 Abs: Pg:

In vivo aortic uptake of MDA2 an oxidation-specific monoclonal antibody highly correlates with atheroosclerotic burden
Periodical: Journal of the American College of Cardiology Index Medicus:
Authors: Tsimikas S, Palinski W, Witztum JL ABS
Yr: 1999 Vol: Nbr: 221A Abs: Pg:

Imaging atherosclerosis with Tc-MDA2 a monoclonal antibody directed to oxidation-specific epitopes in arterial plaque
Periodical: Circulation Index Medicus:
Authors: Tsimikas S, Palinski W, Halpern SA, Curtiss L, Witztum JL ABS
Yr: 1996 Vol: 94 Nbr: I Abs: I-302 Pg: