Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(-/-)/low-density lipoprotein receptor(-/-) mice.
OBJECTIVE
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.
Schiopu
Alexandru
A
Department of Clinical Sciences, Malmö University Hospital, Lund University, Malmö, Sweden.
Frendéus
Björn
B
Jansson
Bo
B
Söderberg
Ingrid
I
Ljungcrantz
Irena
I
Araya
Zufan
Z
Shah
Prediman K
PK
Carlsson
Roland
R
Nilsson
Jan
J
Fredrikson
Gunilla Nordin
GN
D000071479:APOBEC-1 Deaminase; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D053299:Apolipoprotein B-100 / Q000276:immunology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003564:Cytidine Deaminase / Q000502:physiology; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000276:immunology*; D051131:Receptors, Oxidized LDL / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053299:Apolipoprotein B-100; D007074:Immunoglobulin G; D007155:Immunologic Factors; D010446:Peptide Fragments; D051131:Receptors, Oxidized LDL; D011994:Recombinant Proteins; C524806:apolipoprotein B-100 (661-680), human; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase