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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

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posted on 2021-05-10, 00:23 authored by PM Siegel, I Bojti, N Bassler, J Holien, U Flierl, Xiaowei WangXiaowei Wang, P Waggershauser, X Tonnar, C Vedecnik, C Lamprecht, I Stankova, T Li, T Helbing, D Wolf, N Anto-Michel, LS Mitre, J Ehrlich, L Orlean, I Bender, A Przewosnik, M Mauler, L Hollederer, M Moser, C Bode, MW Parker, Karlheinz PeterKarlheinz Peter, P Diehl
The monocyte β -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 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. 2 M


Patrick Siegel was supported by a Fellowship from the German Cardiological Society (DGK) and Philipp Diehl by a Fellowship from the German Research Foundation (DFG) and Monash University. Philipp Diehl and Istvan Bojti received a grant from the German Heart Research Foundation. Jessica Holien was supported by a joint Cure Cancer/Leukaemia Foundation Postdoctoral Fellowship. Karlheinz Peter was supported by the National Health and Medical Research Council of Australia (NHMRC) and the Australian Research Council (ARC). Michael Parker was supported by the National Health and Medical Research Council of Australia (NHMRC) and the Australian Cancer Research Foundation. Dennis Wolf received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 853425) and from the "Else Kroner-Fresenius-Stiftung" (2019_A22).


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Basic Research in Cardiology





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