A DARPin targeting activated Mac-1 is a novel diagnostic tool and potential anti-inflammatory agent in myocarditis, sepsis and myocardial infarction
Patrick M Siegel, Istvan 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 Show all
BASIC RESEARCH IN CARDIOLOGY | SPRINGER HEIDELBERG | Published : 2021
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 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 model..View full abstract
Awarded by European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program
Awarded by Else Kroner-Fresenius-Stiftung
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).