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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. Supported by grants from the Swedish Medical Research Council; Swedish Heart-Lung Foundation; Crafoord Foundation; Royal Physiographic Society; Albert Påhlsson Foundation, Malmö University Hospital Foundation; Lundström Foundation; Heart Foundation; and the United Hostesses at Cedars-Sinai

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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