The first case of COVID-19 treated with the complement C3 inhibitor AMY-101

Mastaglio, Sara; Ruggeri, Annalisa; Risitano, Antonio M.; Angelillo, Piera; Yancopoulou, Despina; Mastellos, Dimitrios C.; Huber‐Lang, Markus; Piemontese, Simona; Assanelli, Andrea; Garlanda, Cecilia; Lambris, John D.; Ciceri, Fabio

doi:10.1016/j.clim.2020.108450

Cited by 272 publications

(294 citation statements)

References 18 publications

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“…The use of the C3 inhibitor AMY-101 in one patient with COVID-19, who recovered (16), and the C5 activation inhibitor, eculizumab, as adjunctive treatment in four patients, who recovered 17, provide clinical evidence that complement may play a pathogenic role in COVID-19. With few exceptions, complement activity is usually protective during viral infections and critically required to control the pathogen (18).…”

Section: D-e Middle Panelsmentioning

confidence: 97%

SARS-CoV2 drives JAK1/2-dependent local and systemic complement hyper-activation

Yan

Freiwald

Chauss

et al. 2020

Preprint

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Patients with coronavirus disease 2019 (COVID-19) present with a range of devastating acute clinical manifestations affecting the lungs, liver, kidneys and gut. The best-characterized entry receptor for the disease-causing virus SARS-CoV2, angiotensin converting enzyme (ACE) 2, is highly expressed in these tissues. However, the pathways that underlie the disease are still poorly understood. Here we show that the complement system is unexpectedly one of the intracellular pathways most highly induced by SARS-CoV2 infection in lung epithelial and liver cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Modelling the regulome of host genes induced by COVID-19 and the drugs that could normalize these genes both implicated the JAK1/2-STAT1 signaling system downstream of type I interferon receptors, and NF-kB. Ruxolitinib, a JAK1/2 inhibitor and the top predicted pharmaceutical candidate, normalized interferon signature genes, IL-6 (the best characterized severity marker in COVID-19) and all complement genes induced by SARS-CoV2, but did not affect NF-kB-regulated genes. We predict that combination therapy with JAK inhibitors and other agents with the potential to normalize NF-kB-signaling, such as anti-viral agents, may serve as an effective clinical strategy.

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Section: D-e Middle Panelsmentioning

confidence: 97%

SARS-CoV2 drives JAK1/2-dependent local and systemic complement hyper-activation

Yan

Freiwald

Chauss

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Since C3 and the lectin pathway have been implicated in the pathophysiology of coronavirus infections, inhibitors of proximal complement pathways, under clinical development for complement‐mediated TMAs, could also be efficacious in COVID‐19 infections. The first case report of C3 inhibition with the compstatin‐based inhibitor AMY‐101 has shown safety and efficacy in severe COVID‐19 15 . Clinical data are needed to provide novel insights in these patients.…”

Section: Management Of Tmamentioning

confidence: 99%

Severe COVID‐19 infection and thrombotic microangiopathy: success does not come easily

2020

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Recent evidence suggests that signs and symptoms of severe COVID-19 infection resemble more the pathophysiology and phenotype of complement-mediated thrombotic microangiopathies (TMA), rather than sepsis-induced coagulopathy or disseminated intravascular coagulation (DIC). 1,2 Since effective treatment is available for complement-mediated TMA, 3 we aim to systematically describe relevant features (clinical phenotype, pathophysiology and management) in patients with severe COVID-19 infection.

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“…SARS-CoV-1 has been reported to induce the up-regulation of C3 (Danesh et al, 2011). Furthermore, because C3-de cient mice infected with SARS-CoV-1 were reported to exhibit less respiratory dysfunction (Gralinski et al, 2018), the inhibition of C3 was also considered a potential target to alleviate the in ammatory lung complications of SARS-CoV-2 infection (Mastaglio et al, 2020;Risitano et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of single-cell mRNA-seq of SARS-CoV-1 and SARS-CoV-2 infection compared to MERS-CoV from Sequence Read Archive (SRA) database reveals novel targets for therapies

Wang

Lü

2020

Preprint

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The global pandemic of COVID-19 caused by SARS-CoV-2 is still threatening the world. By May 13, 2020, more than 40 million people have been infected by SARS-CoV-2 and almost 300 thousand deaths were reported. The discovery and development of anti-viral drugs and vaccines are being conducted worldwide and the understanding of the molecular responses of a single cell to SARS-CoV-2 is in urgent need. The comparative analysis of gene expression in SARS-CoVs and MERS-CoV infected Calu-3 cells reveals that although the coronaviruses cause similar acute respiratory distress syndromes, the molecular responses of Calu-3 cells to SARS-CoVs infections showed a unique signature. A total of 64 correlated differentially expressed genes (DEGs) were identified in this study. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that the DEGs were significantly involved in biological process of ‘Response to interferon-γ’, ‘Viral life cycle’, ‘Phagosome’ and ‘Epstein-Barr virus infection’. STRING analysis showed that the DEGs that were up-regulated after SARS-CoVs infections but down-regulated after MERS-CoV infections showed a strong interaction network. Molecular Complex Detection (MCODE) analysis further refined a unique network consisted of eight hub genes out of 64 DEGs, which are involved in cytokine response (CXCL8, CCL20, and CSF2), ISGylation (ISG15), macrophage activation (ITGAM), complement system (C3), and NFκB signaling pathway (TRAF1 and NFκB2). The unique network identified here will be a potential fingerprint for distinguishing SARS-CoVs infections from MERS-CoV infection. The identification of the eight hub genes will lead to the discovery of new possible therapeutic targets for fighting COVID-19.

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The first case of COVID-19 treated with the complement C3 inhibitor AMY-101

Cited by 272 publications

References 18 publications

SARS-CoV2 drives JAK1/2-dependent local and systemic complement hyper-activation

SARS-CoV2 drives JAK1/2-dependent local and systemic complement hyper-activation

Severe COVID‐19 infection and thrombotic microangiopathy: success does not come easily

Bioinformatics analysis of single-cell mRNA-seq of SARS-CoV-1 and SARS-CoV-2 infection compared to MERS-CoV from Sequence Read Archive (SRA) database reveals novel targets for therapies

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