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A DARPin targeting activated Mac-1 is a novel diagnostic tool and potential anti-inflammatory agent in myocarditis, sepsis and myocardial infarction.
- Source :
-
Basic research in cardiology [Basic Res Cardiol] 2021 Mar 15; Vol. 116 (1), pp. 17. Date of Electronic Publication: 2021 Mar 15. - Publication Year :
- 2021
-
Abstract
- The monocyte β <subscript>2</subscript> -integrin Mac-1 is crucial for leukocyte-endothelium interaction, rendering it an attractive therapeutic target for acute and chronic inflammation. Using phage display, a Designed-Ankyrin-Repeat-Protein (DARPin) was selected as a novel binding protein targeting and blocking the α <subscript>M</subscript> I-domain, an activation-specific epitope of Mac-1. This DARPin, named F7, specifically binds to activated Mac-1 on mouse and human monocytes as determined by flow cytometry. Homology modelling and docking studies defined distinct interaction sites which were verified by mutagenesis. Intravital microscopy showed reduced leukocyte-endothelium adhesion in mice treated with this DARPin. Using mouse models of sepsis, myocarditis and ischaemia/reperfusion injury, we demonstrate therapeutic anti-inflammatory effects. Finally, the activated Mac-1-specific DARPin is established as a tool to detect monocyte activation in patients receiving extra-corporeal membrane oxygenation, as well as suffering from sepsis and ST-elevation myocardial infarction. The activated Mac-1-specific DARPin F7 binds preferentially to activated monocytes, detects inflammation in critically ill patients, and inhibits monocyte and neutrophil function as an efficient new anti-inflammatory agent.
- Subjects :
- Animals
Cell Surface Display Techniques
Cells, Cultured
Designed Ankyrin Repeat Proteins genetics
Disease Models, Animal
Epitopes
Extracorporeal Membrane Oxygenation
Humans
Macrophage-1 Antigen genetics
Macrophages drug effects
Macrophages immunology
Macrophages metabolism
Molecular Docking Simulation
Monocytes immunology
Monocytes metabolism
Myocardial Infarction immunology
Myocardial Infarction metabolism
Myocardial Infarction physiopathology
Myocarditis immunology
Myocarditis metabolism
Myocarditis physiopathology
Myocardium immunology
Myocardium pathology
Proof of Concept Study
Protein Binding
ST Elevation Myocardial Infarction immunology
ST Elevation Myocardial Infarction metabolism
Sepsis immunology
Sepsis metabolism
Sepsis physiopathology
Ventricular Function, Left drug effects
Anti-Inflammatory Agents pharmacology
Designed Ankyrin Repeat Proteins pharmacology
Macrophage-1 Antigen metabolism
Monocytes drug effects
Myocardial Infarction drug therapy
Myocarditis drug therapy
Myocardium metabolism
Sepsis drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1435-1803
- Volume :
- 116
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Basic research in cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 33721106
- Full Text :
- https://doi.org/10.1007/s00395-021-00849-9