Author:
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
Abstract
AbstractThe monocyte β2-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 αM 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.
Funder
Deutsche Forschungsgemeinschaft
Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung.
National Health and Medical Research Council
Deutsche Stiftung für Herzforschung
Leukemia Foundation
European Research Council
Publisher
Springer Science and Business Media LLC
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
Cited by
11 articles.
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