TY - JOUR
T1 - Human oxidation-specific antibodies reduce foam cell formation and atherosclerosis progression
AU - Tsimikas, Sotirios
AU - Miyanohara, Atsushi
AU - Hartvigsen, Karsten
AU - Merki, Esther
AU - Shaw, Peter X
AU - Chou, Meng-Yun
AU - Pattison, Jennifer
AU - Torzewski, Michael
AU - Sollors, Janina
AU - Friedmann, Theodore
AU - Lai, N Chin
AU - Hammond, H Kirk
AU - Getz, Godfrey S
AU - Reardon, Catherine A
AU - Li, Andrew C
AU - Banka, Carole L
AU - Witztum, Joseph L
N1 - Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PY - 2011/10/11
Y1 - 2011/10/11
N2 - Objectives: We sought to assess the in vivo importance of scavenger receptor (SR)mediated uptake of oxidized low-density lipoprotein (OxLDL) in atherogenesis and to test the efficacy of human antibody IK17-Fab or IK17 single-chain Fv fragment (IK17-scFv), which lacks immunologic properties of intact antibodies other than the ability to inhibit uptake of OxLDL by macrophages, to inhibit atherosclerosis. Background: The unregulated uptake of OxLDL by macrophage SR contributes to foam cell formation, but the importance of this pathway in vivo is uncertain. Methods: Cholesterol-fed low-density lipoprotein receptor knockout (LDLR-/-) mice were treated with intraperitoneal infusion of human IK17-Fab (2.5 mg/kg) 3 times per week for 14 weeks. Because anti-human antibodies developed in these mice, LDLR -/-/low-density lipoprotein receptor Rag 1 double-knockout mice (lacking the ability to make immunoglobulins due to loss of T- and B-cell function) were treated with an adenoviral vector encoding adenovirus expressed (Adv)IK17-scFv or control adenovirus-enhanced green fluorescent protein vector intravenously every 2 weeks for 16 weeks. Results: In LDLR-/- mice, infusion of IK17-Fab was able to sustain IK17 plasma levels for the first 8 weeks, but these diminished afterward due to increasing murine anti-IK17 antibody titers. Despite this, after 14 weeks, a 29% decrease in en face atherosclerosis was noted compared with phosphate-buffered salinetreated mice. In LDLR-/-/low-density lipoprotein receptor Rag 1 double-knockout mice, sustained levels of plasma IK17-scFv was achieved by Adv-IK17-scFvmediated hepatic expression, which led to a 46% reduction (p < 0.001) in en face atherosclerosis compared with adenovirus-enhanced green fluorescent protein vector. Importantly, peritoneal macrophages isolated from Adv-IK17-scFv treated mice had decreased lipid accumulation compared with adenovirus-enhanced green fluorescent proteintreated mice. Conclusions: These data support an important role for SR-mediated uptake of OxLDL in the pathogenesis of atherosclerosis and demonstrate that oxidation-specific antibodies reduce the progression of atherosclerosis, suggesting their potential in treating cardiovascular disease in humans.
AB - Objectives: We sought to assess the in vivo importance of scavenger receptor (SR)mediated uptake of oxidized low-density lipoprotein (OxLDL) in atherogenesis and to test the efficacy of human antibody IK17-Fab or IK17 single-chain Fv fragment (IK17-scFv), which lacks immunologic properties of intact antibodies other than the ability to inhibit uptake of OxLDL by macrophages, to inhibit atherosclerosis. Background: The unregulated uptake of OxLDL by macrophage SR contributes to foam cell formation, but the importance of this pathway in vivo is uncertain. Methods: Cholesterol-fed low-density lipoprotein receptor knockout (LDLR-/-) mice were treated with intraperitoneal infusion of human IK17-Fab (2.5 mg/kg) 3 times per week for 14 weeks. Because anti-human antibodies developed in these mice, LDLR -/-/low-density lipoprotein receptor Rag 1 double-knockout mice (lacking the ability to make immunoglobulins due to loss of T- and B-cell function) were treated with an adenoviral vector encoding adenovirus expressed (Adv)IK17-scFv or control adenovirus-enhanced green fluorescent protein vector intravenously every 2 weeks for 16 weeks. Results: In LDLR-/- mice, infusion of IK17-Fab was able to sustain IK17 plasma levels for the first 8 weeks, but these diminished afterward due to increasing murine anti-IK17 antibody titers. Despite this, after 14 weeks, a 29% decrease in en face atherosclerosis was noted compared with phosphate-buffered salinetreated mice. In LDLR-/-/low-density lipoprotein receptor Rag 1 double-knockout mice, sustained levels of plasma IK17-scFv was achieved by Adv-IK17-scFvmediated hepatic expression, which led to a 46% reduction (p < 0.001) in en face atherosclerosis compared with adenovirus-enhanced green fluorescent protein vector. Importantly, peritoneal macrophages isolated from Adv-IK17-scFv treated mice had decreased lipid accumulation compared with adenovirus-enhanced green fluorescent proteintreated mice. Conclusions: These data support an important role for SR-mediated uptake of OxLDL in the pathogenesis of atherosclerosis and demonstrate that oxidation-specific antibodies reduce the progression of atherosclerosis, suggesting their potential in treating cardiovascular disease in humans.
U2 - 10.1016/j.jacc.2011.07.017
DO - 10.1016/j.jacc.2011.07.017
M3 - Journal article
C2 - 21982317
SN - 0735-1097
VL - 58
SP - 1715
EP - 1727
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 16
ER -
