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A monoclonal autoantibody against a cryptic epitope on tissue-adherent low-density lipoprotein for molecular imaging in atherosclerosis

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Title: A monoclonal autoantibody against a cryptic epitope on tissue-adherent low-density lipoprotein for molecular imaging in atherosclerosis
Authors: Khamis, R
Hartley, A
Caga-Anan, M
Pandey, S
Marceddu, C
Kojima, C
Chang, S-H
Boyle, JJ
Johnson, JL
Björkbacka, H
Guo, L
Finn, AV
Virmani, R
Nilsson, J
Haskard, D
Item Type: Journal Article
Abstract: Objectives We aimed to generate and characterize IgG monoclonal autoantibodies in atherosclerosis for targeting of novel molecular determinants. Background Antibody-based constructs for molecular imaging and therapeutic delivery provide promising opportunities for the diagnosis and treatment of atherosclerosis. Methods We created hybridomas from an unimmunized LDL receptor-deficient (Ldlr-/-) mouse and selected an IgG2b isotype autoantibody, LO9, for further characterization. Results LO9 reacted well with native LDL bound to immobilized matrix components, and less well to oxidized LDL. LO9 binding to immobilized native LDL was not neutralized by fluid-phase native LDL, indicating an adhesion-dependent epitope. We localized the epitope to a 20 amino-acid peptide sequence (P5) in the globular amino-terminus of apolipoprotein B. LO9 reacted with antigen in mouse atherosclerosis and in both human stable and ruptured coronary atherosclerosis. Furthermore, in vivo near-infrared fluorescence molecular tomographic imaging and ex vivo confocal microscopy showed that intravenously injected LO9 localized beneath endothelium of the aortic arch in Ldlr-/- mice, in the vicinity of macrophages. Conclusions We believe LO9 is the first example of an IgG autoantibody that reacts with a native LDL epitope revealed by adherence to tissue matrix. Antibodies against adherent native LDL have potential as molecular targeting agents for imaging of and therapeutic delivery to atherosclerosis.
Date of Acceptance: 9-Feb-2022
URI: http://hdl.handle.net/10044/1/96025
ISSN: 1876-7591
Publisher: Elsevier
Journal / Book Title: JACC: Cardiovascular Imaging
Sponsor/Funder: Wellcome Trust
British Heart Foundation
Funder's Grant Number: FS/17/16/32560
Keywords: Cardiovascular System & Hematology
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
Publication Status: Accepted
Embargo Date: Embargoed for 12 months after publication date
Appears in Collections:National Heart and Lung Institute



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