Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19

Amsterdam UMC COVID-19 Biobank

doi:10.26508/lsa.202302106

Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19

Amsterdam UMC COVID-19 Biobank

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	e202302106
Journal	Life Science Alliance
Volume	6
Issue number	11
DOIs	https://doi.org/10.26508/lsa.202302106
Publication status	Published - Nov 2023

Bibliographical note

Publisher Copyright:
© 2023 Geyer et al.

Funding

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).

Funders	Funder number
CVON GENIUS	2019B016, 2015B002, GENIUSII 2017-20
Horizon 2020 Framework Programme	847551
Fondation Leducq	16CVD01, 09120011910025
ZonMw	24184, 10430 01 201 0008
Hartstichting
Innovative Medicines Initiative	831434

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e202302106.fullFinal published version, 2.5 MBLicence: CC BY

Cite this

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title = "Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19",

abstract = "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.",

author = "{Amsterdam UMC COVID-19 Biobank} and Geyer, {Chiara E.} and Chen, {Hung Jen} and Bye, {Alexander P.} and Manz, {Xue D.} and Denise Guerra and Caniels, {Tom G.} and Bijl, {Tom P.L.} and Griffith, {Guillermo R.} and Willianne Hoepel and {de Taeye}, {Steven W.} and Jennifer Veth and Vlaar, {Alexander P.J.} and Gestur Vidarsson and Bogaard, {Harm Jan} and Jurjan Aman and Gibbins, {Jonathan M.} and {van Gils}, {Marit J.} and {de Winther}, {Menno P.J.} and {den Dunnen}, Jeroen",

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year = "2023",

month = nov,

doi = "10.26508/lsa.202302106",

language = "English",

volume = "6",

journal = "Life Science Alliance",

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AU - Amsterdam UMC COVID-19 Biobank

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AU - Bye, Alexander P.

AU - Manz, Xue D.

AU - Guerra, Denise

AU - Caniels, Tom G.

AU - Bijl, Tom P.L.

AU - Griffith, Guillermo R.

AU - Hoepel, Willianne

AU - de Taeye, Steven W.

AU - Veth, Jennifer

AU - Vlaar, Alexander P.J.

AU - Vidarsson, Gestur

AU - Bogaard, Harm Jan

AU - Aman, Jurjan

AU - Gibbins, Jonathan M.

AU - van Gils, Marit J.

AU - de Winther, Menno P.J.

AU - den Dunnen, Jeroen

PY - 2023/11

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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.

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Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19

Abstract

Bibliographical note

Funding

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