Yury I Miller1, Sotirios Tsimikas. 1. Department of Medicine, University of California San Diego, La Jolla, California, USA.
Abstract
PURPOSE OF REVIEW: Emerging data demonstrate the potential of translational applications of antibodies directed against oxidation-specific epitopes (OSEs). 'Biotheranostics' as used in this context in cardiovascular disease (CVD) describes targeting of OSEs for biomarker, therapeutic and molecular imaging diagnostic applications. RECENT FINDINGS: Atherogenesis can be viewed as a chronic, maladaptive inflammatory response to OSE and related antigens. Lipid oxidation collectively yields a large variety of OSE, such as oxidized phospholipids (OxPL) and malondialdehyde epitopes. OSEs are immunogenic, proinflammatory, proatherogenic and plaque destabilizing and represent danger-associated molecular patterns (DAMPs). DAMPs are recognized by the innate immune system via pattern recognition receptors, including scavenger receptors, IgM natural antibodies and complement factor H, which bind, neutralize and/or facilitate their clearance. Biomarker assays measuring OxPL present on apolipoprotein B-100 lipoproteins, and particularly on lipoprotein (a), predict the development of CVD events. In contrast, OxPL on plasminogen facilitate fibrinolysis and may reduce atherothrombosis. Oxidation-specific antibodies attached to magnetic nanoparticles image lipid-rich, oxidation-rich plaques. Infusion or overexpression of oxidation-specific antibodies reduces the progression of atherosclerosis by potentially neutralizing and clearing OSE and preventing foam cell formation, suggesting similar applications in humans. SUMMARY: Using the accelerating knowledge base and improved understanding of the interplay of oxidation, inflammation and innate and adaptive immunity in atherogenesis, emerging clinical applications of oxidation-specific antibodies may identify, monitor and treat CVD in humans.
PURPOSE OF REVIEW: Emerging data demonstrate the potential of translational applications of antibodies directed against oxidation-specific epitopes (OSEs). 'Biotheranostics' as used in this context in cardiovascular disease (CVD) describes targeting of OSEs for biomarker, therapeutic and molecular imaging diagnostic applications. RECENT FINDINGS: Atherogenesis can be viewed as a chronic, maladaptive inflammatory response to OSE and related antigens. Lipid oxidation collectively yields a large variety of OSE, such as oxidized phospholipids (OxPL) and malondialdehyde epitopes. OSEs are immunogenic, proinflammatory, proatherogenic and plaque destabilizing and represent danger-associated molecular patterns (DAMPs). DAMPs are recognized by the innate immune system via pattern recognition receptors, including scavenger receptors, IgM natural antibodies and complement factor H, which bind, neutralize and/or facilitate their clearance. Biomarker assays measuring OxPL present on apolipoprotein B-100 lipoproteins, and particularly on lipoprotein (a), predict the development of CVD events. In contrast, OxPL on plasminogen facilitate fibrinolysis and may reduce atherothrombosis. Oxidation-specific antibodies attached to magnetic nanoparticles image lipid-rich, oxidation-rich plaques. Infusion or overexpression of oxidation-specific antibodies reduces the progression of atherosclerosis by potentially neutralizing and clearing OSE and preventing foam cell formation, suggesting similar applications in humans. SUMMARY: Using the accelerating knowledge base and improved understanding of the interplay of oxidation, inflammation and innate and adaptive immunity in atherogenesis, emerging clinical applications of oxidation-specific antibodies may identify, monitor and treat CVD in humans.
Authors: David Weismann; Karsten Hartvigsen; Nadine Lauer; Keiryn L Bennett; Hendrik P N Scholl; Peter Charbel Issa; Marisol Cano; Hubert Brandstätter; Sotirios Tsimikas; Christine Skerka; Giulio Superti-Furga; James T Handa; Peter F Zipfel; Joseph L Witztum; Christoph J Binder Journal: Nature Date: 2011-10-05 Impact factor: 49.962
Authors: Sotirios Tsimikas; Masanori Aikawa; Francis J Miller; Elizabeth R Miller; Michael Torzewski; Steven R Lentz; Claes Bergmark; Donald D Heistad; Peter Libby; Joseph L Witztum Journal: Arterioscler Thromb Vasc Biol Date: 2006-11-02 Impact factor: 8.311
Authors: Matthew J Budoff; Naser Ahmadi; Khawar M Gul; Sandy T Liu; Ferdinand R Flores; Jima Tiano; Junichiro Takasu; Elizabeth Miller; Sotirios Tsimikas Journal: Prev Med Date: 2009-06-30 Impact factor: 4.018
Authors: Bonnie Ky; Anne Burke; Sotirios Tsimikas; Megan L Wolfe; Mahlet G Tadesse; Philippe O Szapary; Joseph L Witztum; Garret A FitzGerald; Daniel J Rader Journal: J Am Coll Cardiol Date: 2008-04-29 Impact factor: 24.094
Authors: David Frescas; Christelle M Roux; Semra Aygun-Sunar; Anatoli S Gleiberman; Peter Krasnov; Oleg V Kurnasov; Evguenia Strom; Lauren P Virtuoso; Michelle Wrobel; Andrei L Osterman; Marina P Antoch; Vadim Mett; Olga B Chernova; Andrei V Gudkov Journal: Proc Natl Acad Sci U S A Date: 2017-02-13 Impact factor: 11.205
Authors: Fleur M van der Valk; Siroon Bekkering; Jeffrey Kroon; Calvin Yeang; Jan Van den Bossche; Jaap D van Buul; Amir Ravandi; Aart J Nederveen; Hein J Verberne; Corey Scipione; Max Nieuwdorp; Leo A B Joosten; Mihai G Netea; Marlys L Koschinsky; Joseph L Witztum; Sotirios Tsimikas; Niels P Riksen; Erik S G Stroes Journal: Circulation Date: 2016-08-05 Impact factor: 29.690
Authors: Cristina C Clement; Halima Moncrieffe; Aditi Lele; Ginger Janow; Aniuska Becerra; Francesco Bauli; Fawzy A Saad; Giorgio Perino; Cristina Montagna; Neil Cobelli; John Hardin; Lawrence J Stern; Norman Ilowite; Steven A Porcelli; Laura Santambrogio Journal: JCI Insight Date: 2016-02-25