Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology

No Joon Song; Carter Allen; Anna E. Vilgelm; Brian P. Riesenberg; Kevin P. Weller; Kelsi Reynolds; Karthik B. Chakravarthy; Amrendra Kumar; Aastha Khatiwada; Zequn Sun; Anjun Ma; Yuzhou Chang; Mohamed Yusuf; Anqi Li; Cong Zeng; John P. Evans; Donna Bucci; Manuja Gunasena; Menglin Xu; Namal P.M. Liyanage; Chelsea Bolyard; Maria Velegraki; Shan Lu Liu; Qin Ma; Martin Devenport; Yang Liu; Pan Zheng; Carlos D. Malvestutto; Dongjun Chung; Zihai Li

doi:10.1186/s13045-021-01222-y

Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology

No Joon Song, Carter Allen, Anna E. Vilgelm, Brian P. Riesenberg, Kevin P. Weller, Kelsi Reynolds, Karthik B. Chakravarthy, Amrendra Kumar, Aastha Khatiwada, Zequn Sun, Anjun Ma, Yuzhou Chang, Mohamed Yusuf, Anqi Li, Cong Zeng, John P. Evans, Donna Bucci, Manuja Gunasena, Menglin Xu, Namal P.M. LiyanageChelsea Bolyard, Maria Velegraki, Shan Lu Liu, Qin Ma, Martin Devenport, Yang Liu, Pan Zheng, Carlos D. Malvestutto, Dongjun Chung, Zihai Li^*

^*Corresponding author for this work

Preventive Medicine

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

32 Scopus citations

Abstract

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain–containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy. Methods: Using a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19. Results: Twenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8⁺ T cells, CD4⁺ T cells, and CD56⁺ natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis. Conclusions: Our data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.

Original language	English (US)
Article number	5
Journal	Journal of Hematology and Oncology
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s13045-021-01222-y
State	Published - Dec 2022

Funding

This work was supported in part by National Institutes of Health (NIH) grants, including R01AI077283, R01CA213290 to Z.L; and R37CA233770 to A.E.V. Z.L is also supposed by funding from the Pelotonia Foundation. Research reported in this publication was supported by The Ohio State University Comprehensive Cancer Center (OSUCCC) and the National Institutes of Health (NIH) under grant P30CA016058. This research was made possible through resources, expertise, and support provided by the Pelotonia Institute for Immuno-Oncology (PIIO), which is funded by the Pelotonia community and the OSUCCC. We thank the PIIO and the Immune Monitoring and Discovery Platform for their expertise and contributions relating to collecting, processing, storing, and analyzing the clinical trial correlates outlined herein. We acknowledge the patients who agreed to participate in this clinical trial, as the forward trajectory of science hinges on their support. We acknowledge Oncoimmune (now part of Merck & Co., Inc., Kenilworth, NJ, USA) for designing and supporting the clinical trial, which allowed us to collect samples for our correlative studies. The correlative studies were not part of the original phase III Oncoimmune trial but were done at The Ohio State University trial site after communication of intent and sample collection. We thank the staff and researchers in the PIIO and the Immune Monitoring and Discovery Platform (IMDP) for their support during the course of the study. We appreciate the expert administrative support by Ms. Teresa Kutcher.

Keywords

CD24Fc
COVID-19
Cytokine score
Immunophenotyping
Soluble CD24

ASJC Scopus subject areas

Hematology
Molecular Biology
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s13045-021-01222-y

Cite this

Song, N. J., Allen, C., Vilgelm, A. E., Riesenberg, B. P., Weller, K. P., Reynolds, K., Chakravarthy, K. B., Kumar, A., Khatiwada, A., Sun, Z., Ma, A., Chang, Y., Yusuf, M., Li, A., Zeng, C., Evans, J. P., Bucci, D., Gunasena, M., Xu, M., ... Li, Z. (2022). Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology. Journal of Hematology and Oncology, 15(1), Article 5. https://doi.org/10.1186/s13045-021-01222-y

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title = "Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology",

abstract = "Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain–containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy. Methods: Using a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19. Results: Twenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8+ T cells, CD4+ T cells, and CD56+ natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis. Conclusions: Our data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.",

keywords = "CD24Fc, COVID-19, Cytokine score, Immunophenotyping, Soluble CD24",

author = "Song, {No Joon} and Carter Allen and Vilgelm, {Anna E.} and Riesenberg, {Brian P.} and Weller, {Kevin P.} and Kelsi Reynolds and Chakravarthy, {Karthik B.} and Amrendra Kumar and Aastha Khatiwada and Zequn Sun and Anjun Ma and Yuzhou Chang and Mohamed Yusuf and Anqi Li and Cong Zeng and Evans, {John P.} and Donna Bucci and Manuja Gunasena and Menglin Xu and Liyanage, {Namal P.M.} and Chelsea Bolyard and Maria Velegraki and Liu, {Shan Lu} and Qin Ma and Martin Devenport and Yang Liu and Pan Zheng and Malvestutto, {Carlos D.} and Dongjun Chung and Zihai Li",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s13045-021-01222-y",

language = "English (US)",

volume = "15",

journal = "Journal of Hematology and Oncology",

issn = "1756-8722",

publisher = "BioMed Central",

number = "1",

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Song, NJ, Allen, C, Vilgelm, AE, Riesenberg, BP, Weller, KP, Reynolds, K, Chakravarthy, KB, Kumar, A, Khatiwada, A, Sun, Z, Ma, A, Chang, Y, Yusuf, M, Li, A, Zeng, C, Evans, JP, Bucci, D, Gunasena, M, Xu, M, Liyanage, NPM, Bolyard, C, Velegraki, M, Liu, SL, Ma, Q, Devenport, M, Liu, Y, Zheng, P, Malvestutto, CD, Chung, D & Li, Z 2022, 'Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology', Journal of Hematology and Oncology, vol. 15, no. 1, 5. https://doi.org/10.1186/s13045-021-01222-y

TY - JOUR

T1 - Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology

AU - Song, No Joon

AU - Allen, Carter

AU - Vilgelm, Anna E.

AU - Riesenberg, Brian P.

AU - Weller, Kevin P.

AU - Reynolds, Kelsi

AU - Chakravarthy, Karthik B.

AU - Kumar, Amrendra

AU - Khatiwada, Aastha

AU - Sun, Zequn

AU - Ma, Anjun

AU - Chang, Yuzhou

AU - Yusuf, Mohamed

AU - Li, Anqi

AU - Zeng, Cong

AU - Evans, John P.

AU - Bucci, Donna

AU - Gunasena, Manuja

AU - Xu, Menglin

AU - Liyanage, Namal P.M.

AU - Bolyard, Chelsea

AU - Velegraki, Maria

AU - Liu, Shan Lu

AU - Ma, Qin

AU - Devenport, Martin

AU - Liu, Yang

AU - Zheng, Pan

AU - Malvestutto, Carlos D.

AU - Chung, Dongjun

AU - Li, Zihai

PY - 2022/12

Y1 - 2022/12

N2 - Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain–containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy. Methods: Using a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19. Results: Twenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8+ T cells, CD4+ T cells, and CD56+ natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis. Conclusions: Our data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.

AB - Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain–containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy. Methods: Using a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19. Results: Twenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8+ T cells, CD4+ T cells, and CD56+ natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis. Conclusions: Our data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.

KW - CD24Fc

KW - COVID-19

KW - Cytokine score

KW - Immunophenotyping

KW - Soluble CD24

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UR - http://www.scopus.com/inward/citedby.url?scp=85122760019&partnerID=8YFLogxK

U2 - 10.1186/s13045-021-01222-y

DO - 10.1186/s13045-021-01222-y

M3 - Article

C2 - 35012610

AN - SCOPUS:85122760019

SN - 1756-8722

VL - 15

JO - Journal of Hematology and Oncology

JF - Journal of Hematology and Oncology

IS - 1

M1 - 5

ER -

Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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