Monoclonal Autoantibody Against a Cryptic Epitope on Tissue-Adherent Low-Density Lipoprotein for Molecular Imaging in Atherosclerosis

Ramzi Y. Khamis, Adam Hartley, Mikhail Caga-Anan, Samata S. Pandey, Cinzia Marceddu, Chiari Kojima, Shang Hung Chang, Joseph J. Boyle, Jason L. Johnson, Harry Björkbacka, Liang Guo, Aloke V. Finn, Renu Virmani, Jan Nilsson, Dorian O. Haskard*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

2 Scopus citations

Abstract

Background: Antibody-based constructs for molecular imaging and therapeutic delivery provide promising opportunities for the diagnosis and treatment of atherosclerosis. Objectives: The authors aimed to generate and characterize immunoglobulin (Ig)G monoclonal autoantibodies in atherosclerosis for targeting of novel molecular determinants. Methods: The authors created hybridomas from an unimmunized low-density lipoprotein (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. The authors 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: The authors 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.

Original languageEnglish
Pages (from-to)1458-1470
Number of pages13
JournalJACC: Cardiovascular Imaging
Volume15
Issue number8
DOIs
StatePublished - 08 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Authors

Keywords

  • atherosclerosis
  • lipids and cholesterol
  • molecular imaging

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