A DARPin targeting activated Mac-1 is a novel diagnostic tool and potential anti-inflammatory agent in myocarditis, sepsis and myocardial infarction
Year: 2021
Type: article
Abstract: The 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 αMI-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.
Source: Basic Research in Cardiology
Authors: Patrick M. Siegel, István Bojti, Nicole Bassler, Jessica Holien, Ulrike Flierl, Xiaowei Wang, Philipp Waggershauser, Xavier Tonnar, Christopher Vedecnik, Constanze Lamprecht, Ivana Stankova, Tian Li, Thomas Helbing, Dennis Wolf, Nathaly Anto-Michel, Lucia Sol Mitre, Julia Ehrlich, Lukas Orlean, Ileana Bender, Anne Przewosnik, Maximilian Mauler, Laura Hollederer, Martin Moser, Christoph Bode, Michael W. Parker, Karlheinz Peter, Philipp Diehl
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: European Commission, Australian Cancer Research Foundation, Deutsche Forschungsgemeinschaft, Monash University, State Government of Victoria, Deutsche Stiftung für Herzforschung, Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung., Baker Heart and Diabetes Institute, European Research Council, National Health and Medical Research Council
OpenAlex ID: W3137617893