title: Human oxidation-specific antibodies reduce foam cell formation and atherosclerosis progression.
abstract: OBJECTIVE
  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 saline-treated mice. In LDLR(-/-)/low-density lipoprotein receptor Rag 1 double-knockout mice, sustained levels of plasma IK17-scFv was achieved by Adv-IK17-scFv-mediated 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 protein-treated 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.
authors: Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0682, USA. stsimikas@ucsd.edu
authors: Sotirios
authors: S
authors: Tsimikas
authors: Atsushi
authors: A
authors: Miyanohara
authors: Karsten
authors: K
authors: Hartvigsen
authors: Esther
authors: E
authors: Merki
authors: Peter X
authors: PX
authors: Shaw
authors: Meng-Yun
authors: MY
authors: Chou
authors: Jennifer
authors: J
authors: Pattison
authors: Michael
authors: M
authors: Torzewski
authors: Janina
authors: J
authors: Sollors
authors: Theodore
authors: T
authors: Friedmann
authors: N Chin
authors: NC
authors: Lai
authors: H Kirk
authors: HK
authors: Hammond
authors: Godfrey S
authors: GS
authors: Getz
authors: Catherine A
authors: CA
authors: Reardon
authors: Andrew C
authors: AC
authors: Li
authors: Carole L
authors: CL
authors: Banka
authors: Joseph L
authors: JL
authors: Witztum
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D018450:Disease Progression; D005487:Foam Cells / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D000906:Antibodies; D018398:Homeodomain Proteins; D007128:Immunoglobulin Fragments; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D011994:Recombinant Proteins; C099252:oxidized low density lipoprotein; C064658:RAG-1 protein; D049452:Green Fluorescent Proteins