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Lookup NU author(s): Yasemin Ekinci, Professor Gavin RichardsonORCiD, Professor Ioakim SpyridopoulosORCiD
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ST-elevation myocardial infarction (STEMI) is the most dramatic complication of coronary artery disease and is associated with a high morbidity and mortality rate worldwide. Immediate reperfusion is critical to restore blood flow to the heart, limit infarct size, and reduce the risk of post-STEMI complications, thereby improving long-term survival. However, reperfusion therapy itself is thought to eventually cause further damage to the myocardium, known as reperfusion injury, which enhances the already existing inflammatory response. This immune response can lead to adverse left ventricular remodelling and heart failure in the mid-and long term. Therefore, specific treatment targets are required to reduce excessive inflammation while maintaining immune defence. We have previously shown in 1,300 STEMI patients that immune cells, specifically T cells, are significantly decreased within minutes of reperfusion therapy, which may correlate closely with pathophysiological conditions. This significant reduction was observed in all cells expressing CX3CR1, the receptor for fractalkine. Fractalkine (FKN, CX3CL1) is a member of the chemokine family that facilitates the extravasation and recruitment of CX3CR1-expressing lymphocytes to sites of tissue inflammation. Thus, blocking fractalkine/CX3CR1 signaling is suggested as a promising anti-inflammatory strategy for the treatment of both acute and chronic cardiovascular disease. KAND567, a KANCERA AB drug candidate, is a small molecule, selective, non-competitive, allosteric antagonist of CX3CR1 and has been used as IMP (Investigational Medicinal Product) for this clinical phase IIa study in STEMI patients (ISRCTN 18402242). The aim of this project is to investigate the dynamic changes in immune cell count and CX3CR1 expression after intravenous and oral administration of KAND567 to STEMI patients undergoing primary percutaneous coronary intervention (PPCI). This study is a randomized, 2-arm, parallel-group, placebo-controlled, double-blind, multi-centre Phase IIa clinical trial, "FRACTAL Trial". Blood sampling was at nine-time points, including baseline (before IM administration), bolus (after IMP administration), 90 mins, 180 mins, 1 day, 3 days, 6 days, 30 days and 90 days., The leukocyte kinetics in 71 STEMI patients was analysed using flow cytometry. The highest CX3CR1 receptor density at baseline was observed in CD4 and CD8+T cell subsets. Following different time points, CX3CR1 MFI in the CD8+ compartment remained low until day 6. In addition, CX3CR1-expressing effector T cell subsets, monocytes and NK cells decreased 90 mins after administration of IMP and recovered rapidly for up to 24 hours. Effector T-cells drop substantially after reperfusion only in some patients. One possible explanation for this may be that KAND567 binds CX3CR1-expressing effector T-cell subsets, monocytes, and NK cells in the peripheral blood, preventing their migration to the heart and thus reducing the decrease in cell numbers in the peripheral blood. Another possible explanation could be that previously depleted cells return to circulation.
Author(s): Ekinci Y, Richardson GD, Spyridopoulos I
Publication type: Article
Publication status: Published
Journal: Journal of Pharmacology and Experimental Therapeutics
Year: 2024
Volume: 389
Issue: S3
Print publication date: 01/06/2024
Online publication date: 13/05/2024
Acceptance date: 01/03/2024
ISSN (print): 0022-3565
ISSN (electronic): 1521-0103
Publisher: American Society for Pharmacology and Experimental Therapeutics
URL: https://doi.org/10.1124/jpet.472.935010
DOI: 10.1124/jpet.472.935010
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