title: Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions.
abstract: BACKGROUND
  Immunization with oxidized LDL (oxLDL) reduces atherosclerosis in rodents. We tested the hypothesis that treatment with a human recombinant monoclonal antibody against oxLDL will reduce the burden or composition of atherosclerotic lesions in hypercholesterolemic minipigs.
  
  
  RESULTS
  Thirty-eight hypercholesterolemic minipigs with defective LDL receptors were injected with an oxLDL antibody or placebo weekly for 12weeks. An 18F-fluorodeoxyglucose positron emission tomography (FDG PET) scan (n=9) was performed before inclusion and after 3months of treatment. Blood samples were obtained prior to each injection. Following the last injection all animals were sacrificed, and the heart, aorta, and iliac arteries were removed. The left anterior descending coronary artery was sectioned at 5mm intervals for quantitative and qualitative assessments of atherosclerosis, including immunohistochemical phenotyping of macrophages using a pan-macrophage marker (CD68) and markers for putative pro-atherogenic (cathepsin S) and atheroprotective (CD163) macrophages. Aorta, right coronary artery, and left iliac artery were stained en face with Sudan IV and the amount of atherosclerosis quantified. There was no effect of treatment on plasma lipid profile, vascular FDG-PET signal or the amount of atherosclerosis in any of the examined arteries. However, immunostaining of coronary lesions revealed reduced cathepsin S positivity in the treated group compared with placebo (4.8% versus 8.2% of intima area, p=0.03) with no difference in CD68 or CD163 positivity.
  
  
  CONCLUSIONS
  In hypercholesterolemic minipigs, treatment with a human recombinant monoclonal antibody against oxLDL reduced cathepsin S in coronary lesions without any effect on the burden of atherosclerosis or aortic FDG-PET signal.
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: cbpoulsen@clin.au.dk.
authors.forename: Christian Bo
authors.initials: CB
authors.lastname: Poulsen
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Ahmed Ludvigsen
authors.initials: AL
authors.lastname: Al-Mashhadi
authors.affiliation: Truly Translational, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: von Wachenfeldt
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Jacob Fog
authors.initials: JF
authors.lastname: Bentzon
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lars Bo
authors.initials: LB
authors.lastname: Nielsen
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Rozh H
authors.initials: RH
authors.lastname: Al-Mashhadi
authors.affiliation: Department of Clinical Engineering, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Thygesen
authors.affiliation: Department of Nuclear Medicine and PET-Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Tolbod
authors.affiliation: Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jens Rolighed
authors.initials: JR
authors.lastname: Larsen
authors.affiliation: Department of Nuclear Medicine and PET-Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Frøkiær
authors.affiliation: Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Tawakol
authors.affiliation: Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Esad
authors.initials: E
authors.lastname: Vucic
authors.affiliation: Genentech, Inc., San Francisco, United States.
authors.forename: Jill
authors.initials: J
authors.lastname: Fredrickson
authors.affiliation: Genentech, Inc., San Francisco, United States.
authors.forename: Amos
authors.initials: A
authors.lastname: Baruch
authors.affiliation: BioInvent International AB, Lund, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Frendéus
authors.affiliation: BioInvent International AB, Lund, Sweden.
authors.forename: Anna-Karin L
authors.initials: AK
authors.lastname: Robertson
authors.affiliation: Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Søren Kragh
authors.initials: SK
authors.lastname: Moestrup
authors.affiliation: Department of Angiohematology, Hospital Lariboisiere, Paris, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Drouet
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Erling
authors.initials: E
authors.lastname: Falk
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D050197:Atherosclerosis / Q000097:blood* / Q000000981:diagnostic imaging / Q000188:drug therapy*; D002403:Cathepsins / Q000097:blood*; D004195:Disease Models, Animal; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D006937:Hypercholesterolemia / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008055:Lipids / Q000097:blood; D049268:Positron-Emission Tomography / Q000379:methods; D011994:Recombinant Proteins / Q000494:pharmacology*; D013552:Swine; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D008055:Lipids; C000604072:MLDL1278A; D011994:Recombinant Proteins; D019788:Fluorodeoxyglucose F18; D002403:Cathepsins; C028217:cathepsin S
keywords: Antibody; Atherosclerosis; Cholesterol