RT Journal Article
SR Electronic
T1 Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202302106
DO 10.26508/lsa.202302106
VO 6
IS 11
A1 Geyer, Chiara E
A1 Chen, Hung-Jen
A1 Bye, Alexander P
A1 Manz, Xue D
A1 Guerra, Denise
A1 Caniels, Tom G
A1 Bijl, Tom PL
A1 Griffith, Guillermo R
A1 Hoepel, Willianne
A1 de Taeye, Steven W
A1 Veth, Jennifer
A1 Vlaar, Alexander PJ
A1 Amsterdam UMC COVID-19 Biobank
A1 Vidarsson, Gestur
A1 Bogaard, Harm Jan
A1 Aman, Jurjan
A1 Gibbins, Jonathan M
A1 van Gils, Marit J
A1 de Winther, Menno PJ
A1 den Dunnen, Jeroen
YR 2023
UL http://www.life-science-alliance.org/content/6/11/e202302106.abstract
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.