Complement C3 vs C5 inhibition in severe COVID-19 Early clinical findings reveal differential biological efficacy

Complement C3 vs C5 inhibition in severe COVID-19 : Early clinical findings reveal differential biological efficacy

Copyright © 2020 Elsevier Inc. All rights reserved.

Bibliographische Detailangaben
Veröffentlicht in:Clinical immunology (Orlando, Fla.). - 1999. - 220(2020) vom: 01. Nov., Seite 108598
1. Verfasser: Mastellos, Dimitrios C (VerfasserIn)
Weitere Verfasser: Pires da Silva, Bruno G P, Fonseca, Benedito A L, Fonseca, Natasha P, Auxiliadora-Martins, Maria, Mastaglio, Sara, Ruggeri, Annalisa, Sironi, Marina, Radermacher, Peter, Chrysanthopoulou, Akrivi, Skendros, Panagiotis, Ritis, Konstantinos, Manfra, Ilenia, Iacobelli, Simona, Huber-Lang, Markus, Nilsson, Bo, Yancopoulou, Despina, Connolly, E Sander, Garlanda, Cecilia, Ciceri, Fabio, Risitano, Antonio M, Calado, Rodrigo T, Lambris, John D
Format: Online-Aufsatz
Sprache:English
Veröffentlicht: 2020
Zugriff auf das übergeordnete Werk:Clinical immunology (Orlando, Fla.)
Schlagworte:Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't AMY-101 Biomarkers C3 inhibition C5 blockade COVID-19 Drug efficacy Eculizumab mehr... Thromboinflammation Antibodies, Monoclonal, Humanized C3 protein, human Complement C3 Complement C5 Complement Inactivating Agents IL6 protein, human Immunologic Factors Interleukin-6 Peptides, Cyclic compstatin C-Reactive Protein 9007-41-4 eculizumab A3ULP0F556
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100 1 |a Mastellos, Dimitrios C  |e verfasserin  |4 aut 
245 1 0 |a Complement C3 vs C5 inhibition in severe COVID-19  |b Early clinical findings reveal differential biological efficacy 
264 1 |c 2020 
336 |a Text  |b txt  |2 rdacontent 
337 |a ƒaComputermedien  |b c  |2 rdamedia 
338 |a ƒa Online-Ressource  |b cr  |2 rdacarrier 
500 |a Date Completed 28.10.2020 
500 |a Date Revised 12.11.2023 
500 |a published: Print-Electronic 
500 |a CommentIn: Clin Immunol. 2020 Dec;221:108603. - PMID 33022386 
500 |a Citation Status MEDLINE 
520 |a Copyright © 2020 Elsevier Inc. All rights reserved. 
520 |a Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials 
650 4 |a Journal Article 
650 4 |a Research Support, N.I.H., Extramural 
650 4 |a Research Support, Non-U.S. Gov't 
650 4 |a AMY-101 
650 4 |a Biomarkers 
650 4 |a C3 inhibition 
650 4 |a C5 blockade 
650 4 |a COVID-19 
650 4 |a Drug efficacy 
650 4 |a Eculizumab 
650 4 |a Thromboinflammation 
650 7 |a Antibodies, Monoclonal, Humanized  |2 NLM 
650 7 |a Biomarkers  |2 NLM 
650 7 |a C3 protein, human  |2 NLM 
650 7 |a Complement C3  |2 NLM 
650 7 |a Complement C5  |2 NLM 
650 7 |a Complement Inactivating Agents  |2 NLM 
650 7 |a IL6 protein, human  |2 NLM 
650 7 |a Immunologic Factors  |2 NLM 
650 7 |a Interleukin-6  |2 NLM 
650 7 |a Peptides, Cyclic  |2 NLM 
650 7 |a compstatin  |2 NLM 
650 7 |a C-Reactive Protein  |2 NLM 
650 7 |a 9007-41-4  |2 NLM 
650 7 |a eculizumab  |2 NLM 
650 7 |a A3ULP0F556  |2 NLM 
700 1 |a Pires da Silva, Bruno G P  |e verfasserin  |4 aut 
700 1 |a Fonseca, Benedito A L  |e verfasserin  |4 aut 
700 1 |a Fonseca, Natasha P  |e verfasserin  |4 aut 
700 1 |a Auxiliadora-Martins, Maria  |e verfasserin  |4 aut 
700 1 |a Mastaglio, Sara  |e verfasserin  |4 aut 
700 1 |a Ruggeri, Annalisa  |e verfasserin  |4 aut 
700 1 |a Sironi, Marina  |e verfasserin  |4 aut 
700 1 |a Radermacher, Peter  |e verfasserin  |4 aut 
700 1 |a Chrysanthopoulou, Akrivi  |e verfasserin  |4 aut 
700 1 |a Skendros, Panagiotis  |e verfasserin  |4 aut 
700 1 |a Ritis, Konstantinos  |e verfasserin  |4 aut 
700 1 |a Manfra, Ilenia  |e verfasserin  |4 aut 
700 1 |a Iacobelli, Simona  |e verfasserin  |4 aut 
700 1 |a Huber-Lang, Markus  |e verfasserin  |4 aut 
700 1 |a Nilsson, Bo  |e verfasserin  |4 aut 
700 1 |a Yancopoulou, Despina  |e verfasserin  |4 aut 
700 1 |a Connolly, E Sander  |e verfasserin  |4 aut 
700 1 |a Garlanda, Cecilia  |e verfasserin  |4 aut 
700 1 |a Ciceri, Fabio  |e verfasserin  |4 aut 
700 1 |a Risitano, Antonio M  |e verfasserin  |4 aut 
700 1 |a Calado, Rodrigo T  |e verfasserin  |4 aut 
700 1 |a Lambris, John D  |e verfasserin  |4 aut 
773 0 8 |i Enthalten in  |t Clinical immunology (Orlando, Fla.)  |d 1999  |g 220(2020) vom: 01. Nov., Seite 108598  |w (DE-627)NLM098196855  |x 1521-7035  |7 nnns 
773 1 8 |g volume:220  |g year:2020  |g day:01  |g month:11  |g pages:108598 
856 4 0 |u http://dx.doi.org/10.1016/j.clim.2020.108598  |3 Volltext 
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