A DARPin targeting activated Mac-1 is a novel diagnostic tool and potential anti-inflammatory agent in myocarditis, sepsis and myocardial infarction

The monocyte β 2 -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 M...

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Bibliographic Details
Published in:Basic research in cardiology 2021-12, Vol.116 (1), p.17, Article 17
Main Authors: Siegel, Patrick M., Bojti, István, Bassler, Nicole, Holien, Jessica, Flierl, Ulrike, Wang, Xiaowei, Waggershauser, Philipp, Tonnar, Xavier, Vedecnik, Christopher, Lamprecht, Constanze, Stankova, Ivana, Li, Tian, Helbing, Thomas, Wolf, Dennis, Anto-Michel, Nathaly, Mitre, Lucia Sol, Ehrlich, Julia, Orlean, Lukas, Bender, Ileana, Przewosnik, Anne, Mauler, Maximilian, Hollederer, Laura, Moser, Martin, Bode, Christoph, Parker, Michael W., Peter, Karlheinz, Diehl, Philipp
Format: Article
Language:English
Subjects:
Animal models
Animals
Ankyrins
Anti-inflammatory agents
Anti-Inflammatory Agents - pharmacology
Cardiology
Cell activation
Cell Surface Display Techniques
Cells, Cultured
Designed Ankyrin Repeat Proteins - genetics
Designed Ankyrin Repeat Proteins - pharmacology
Disease Models, Animal
Endothelium
Epitopes
Extracorporeal Membrane Oxygenation
Flow cytometry
Heart attacks
Heart diseases
Homology
Humans
Inflammation
Ischemia
Leukocytes
Leukocytes (neutrophilic)
Mac1 protein
Macrophage-1 Antigen - genetics
Macrophage-1 Antigen - metabolism
Macrophages - drug effects
Macrophages - immunology
Macrophages - metabolism
Medicine
Medicine & Public Health
Molecular Docking Simulation
Monocytes
Monocytes - drug effects
Monocytes - immunology
Monocytes - metabolism
Mutagenesis
Myocardial infarction
Myocardial Infarction - drug therapy
Myocardial Infarction - immunology
Myocardial Infarction - metabolism
Myocardial Infarction - physiopathology
Myocarditis
Myocarditis - drug therapy
Myocarditis - immunology
Myocarditis - metabolism
Myocarditis - physiopathology
Myocardium - immunology
Myocardium - metabolism
Myocardium - pathology
Original Contribution
Oxygenation
Phage display
Phages
Proof of Concept Study
Protein Binding
Proteins
Reperfusion
Sepsis
Sepsis - drug therapy
Sepsis - immunology
Sepsis - metabolism
Sepsis - physiopathology
ST Elevation Myocardial Infarction - immunology
ST Elevation Myocardial Infarction - metabolism
Therapeutic targets
Ventricular Function, Left - drug effects
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Summary:The monocyte β 2 -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 M 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.
ISSN:0300-8428
1435-1803
DOI:10.1007/s00395-021-00849-9