TY - JOUR
T1 - Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19
AU - Amsterdam UMC Covid-19 Biobank
AU - Geyer, Chiara E.
AU - Chen, Hung Jen
AU - Bye, Alexander P.
AU - Manz, Xue D.
AU - Guerra, Denise
AU - Caniels, Tom G.
AU - Bijl, Tom Pl
AU - Griffith, Guillermo R.
AU - Hoepel, Willianne
AU - de Taeye, Steven W.
AU - Veth, Jennifer
AU - Vlaar, Alexander Pj
AU - Vidarsson, Gestur
AU - Bogaard, Harm Jan
AU - Aman, Jurjan
AU - Gibbins, Jonathan M.
AU - van Gils, Marit J.
AU - de Winther, Menno Pj
AU - den Dunnen, Jeroen
AU - Hollmann, M.W.
N1 - Funding Information: We are grateful for the generous support from the Amsterdam UMC COVID-19 Biobank. J den Dunnen was supported by ZonMw (10430 01 201 0008), Amsterdam Infection and Immunity COVID-19 Grant (24184), AMC Fellowship (2015), European Union’s Horizon 2020 Research and Innovation Programme (847551), and Innovative Medicines Initiative 2 Joint Undertaking Grant (831434). MPJ de Winther was supported by Amsterdam UMC, Amsterdam Cardiovascular Sciences, the Netherlands Heart Foundation (CVON GENIUS and GENIUSII 2017-20), Spark-Holding BV (2015B002 and 2019B016), Fondation Leducq (Transatlantic Network Grant 16CVD01), and ZonMW (09120011910025). Publisher Copyright: © 2023 Geyer et al.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fcγ receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation whereas simultaneously minimizing the inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike-induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.
AB - Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fcγ receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation whereas simultaneously minimizing the inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike-induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.
UR - http://www.scopus.com/inward/record.url?scp=85171119794&partnerID=8YFLogxK
U2 - https://doi.org/10.26508/lsa.202302106
DO - https://doi.org/10.26508/lsa.202302106
M3 - Article
C2 - 37699657
SN - 2575-1077
VL - 6
JO - Life Science Alliance
JF - Life Science Alliance
IS - 11
M1 - e202302106
ER -