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PRECLINICAL STUDY

Recombinant Antibodies to an Oxidized Low-Density Lipoprotein Epitope Induce Rapid Regression of Atherosclerosis in Apobec-1 ^–/–/Low-Density Lipoprotein Receptor^–/– Mice

Alexandru Schiopu, MD, PhD^_*,_*, Björn Frendéus, PhD, Bo Jansson, PhD, Ingrid Söderberg, BSI^_*, Irena Ljungcrantz, BSI^_*, Zufan Araya, PhD, Prediman K. Shah, MD, FACC, Roland Carlsson, PhD, Jan Nilsson, MD, PhD^_* and Gunilla Nordin Fredrikson, PhD^_*,

^_* Department of Clinical Sciences, Malmö University Hospital, Lund University, Malmö, Sweden
BioInvent International AB, Lund, Sweden
Atherosclerosis Research Center and Division of Cardiology, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
Department of Biomedical Laboratory Science, Malmö University, Malmö, Sweden.

Manuscript received May 4, 2007; revised manuscript received July 5, 2007, accepted July 24, 2007.

^_* Reprint requests and correspondence: Dr. Alexandru Schiopu, Transplantation Immunology Unit, Nuffield Department of Surgery, Level 6, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, United Kingdom. (Email: alexandru.schiopu{at}med.lu.se).

Objectives: The present study tested the hypothesis that treatment with human recombinant immunoglobulin G1 (IgG1) antibodies against a specific oxidized low-density lipoprotein (oxLDL) epitope will induce regression of existing atherosclerotic lesions in LDL receptor-deficient mice expressing apolipoprotein B-100 (apoB-100) (Apobec-1 ^–/–/LDLR^–/–).

Background: Oxidized LDL plays an essential role in the pathogenesis of atherosclerosis. We previously showed that an antibody against oxLDL reduces progression of atherosclerosis in mice.

Methods: Apobec-1 ^–/–/LDLR^–/– mice were fed a high-fat diet until they were 24 weeks and were subsequently transferred to chow. Starting at 25 weeks, mice were given 3 weekly injections of either of 2 recombinant human IgG1 antibodies (IEI-E3 or 2D03) against a malondialdehyde-modified apoB-100 peptide sequence.

Results: At 25 weeks, atherosclerotic lesions covered 10.3 ± 3.7% of the descending aorta. Transfer to chow diet resulted in a modest regression of atherosclerosis over a 5-week period (8.28 ± 4.36%; p = NS). Antibody treatment induced additional regression of atherosclerosis by 50% (2D03; p = 0.001) and 36% (IEI-E3; p = 0.004) compared with control IgG1. The 2D03 treatment also reduced plaque inflammation, enhanced plaque expression of the adenosine triphosphate–binding cassette transporter A1, and inhibited expression of monocyte chemoattractant protein-1 in cultured monocytes.

Conclusions: Human IgG1 against a specific oxLDL epitope can induce rapid and substantial regression of atherosclerotic lesions, possibly by stimulating lipid efflux and inhibiting macrophage recruitment. These recombinant human antibodies could represent a novel strategy for rapid regression/stabilization of atherosclerotic lesions.

Abbreviations and Acronyms   ABCA1 = adenosine triphosphate–binding cassette transporter A1   apoB-100 = apolipoprotein B-100   IgG1 = immunoglobulin G1   LDL = low-density lipoprotein   LDLR = low-density lipoprotein receptor   MCP-1 = monocyte chemoattractant protein-1   MDA = malondialdehyde   oxLDL = oxidized low-density lipoprotein

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