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

• DOI: 10.1161/hq0801.093587
• Publication Date: 2007-09-28T18:27:24Z
• Authors: Peter X. Shaw; Sohvi Hörkkö; Sotirios Tsimikas; Mi-Kyung Chang; Wulf Palinski; Gregg J. Silverman; Pojen P. Chen; Joseph L. Witztum
• Keywords: Aging; Arteriosclerosis; Lipoproteins; Clinical Sciences; 610; Clinical sciences; Cardiorespiratory Medicine and Haematology; Cardiovascular; Cardiovascular medicine and haematology; Antibodies; LDL; Epitopes; Immunoglobulin Fab Fragments; 03 medical and health sciences; 0302 clinical medicine; Cardiovascular Medicine and Haematology; Malondialdehyde; Monoclonal; 2.1 Biological and endogenous factors; antibodies; Animals; Humans; Autoantibodies; Biomedical and Clinical Sciences; Macrophages; imaging; Antibodies, Monoclonal; Atherosclerosis; 3. Good health; lipoproteins; Lipoproteins, LDL; Cardiovascular System & Hematology; atherosclerosis; Biotechnology

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 125 I-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.