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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1333.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Human-Derived Anti-Oxidized LDL Autoantibody Blocks Uptake of Oxidized LDL by Macrophages and Localizes to Atherosclerotic Lesions In Vivo

Peter X. Shaw; Sohvi Hörkkö; Sotirios Tsimikas; Mi-Kyung Chang; Wulf Palinski; Gregg J. Silverman; Pojen P. Chen; Joseph L. Witztum

From the Department of Medicine, University of California, San Diego, La Jolla, and the Department of Medicine (P.P.C.), University of California, Los Angeles.

Correspondence to Joseph L. Witztum, MD, Department of Medicine, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0682. E-mail jwitztum{at}ucsd.edu

Abstract—— Autoantibodies to oxidation-specific epitopes of low density lipoprotein (LDL), such as malondialdehyde-modified LDL (MDA-LDL), occur in plasma and atherosclerotic lesions of humans and animals. Plasma titers of such antibodies are correlated with atherosclerosis in murine models, and several such autoantibodies have been cloned. However, human-derived monoclonal antibodies to epitopes of oxidized LDL (OxLDL) have not yet been reported. We constructed a phage display antibody library from a patient with high plasma anti-MDA-LDL titers and isolated 3 monoclonal IgG Fab antibodies, which specifically bound to MDA-LDL. One of these, IK17, also bound to intact OxLDL as well as to its lipid and protein moieties but not to those of native LDL. IK17 inhibited the uptake of OxLDL by macrophages and also bound to apoptotic cells and inhibited their phagocytosis by macrophages. IK17 strongly immunostained necrotic cores of human and rabbit atherosclerotic lesions. When ¹²⁵I-IK17 was injected intravenously into LDL receptor-deficient mice, its specific uptake was greatly enriched in atherosclerotic plaques versus normal aortic tissue. Human autoantibodies to OxLDL have important biological properties that could influence the natural course of atherogenesis.

Key Words: atherosclerosis • imaging • antibodies • lipoproteins

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