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

D.C. Mastellos, B.G.P. Pires da Silva, B.A.L. Fonseca, N.P. Fonseca, M. Auxiliadora-Martins, S. Mastaglio, A. Ruggeri, M. Sironi, P. Radermacher, A. Chrysanthopoulou, P. Skendros, K. Ritis, I. Manfra, S. Iacobelli, M. Huber-Lang, B. Nilsson, D. Yancopoulou, E.S. Connolly, C. Garlanda, F. CiceriA.M. Risitano, R.T. Calado, J.D. Lambris

Research output: Contribution to journalArticlepeer-review


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. © 2020 Elsevier Inc.
Original languageEnglish
JournalClin. Immunol.
Publication statusPublished - 2020


  • AMY-101
  • Biomarkers
  • C3 inhibition
  • C5 blockade
  • COVID-19
  • Drug efficacy
  • Eculizumab
  • Thromboinflammation
  • C reactive protein
  • complement component C3
  • complement component C5
  • D dimer
  • dextro tyrosylisoleucylcysteinylvalyl 1 methyltryptophylglutaminylaspartyltryptophyl n methylglycylalanylhistidylarginylcysteinyl n methylisoleucinamide 3,13 cyclic sulfide
  • eculizumab
  • interleukin 6
  • lactate dehydrogenase
  • thrombin antithrombin complex
  • biological marker
  • C3 protein, human
  • complement inhibitor
  • compstatin
  • cyclopeptide
  • IL6 protein, human
  • immunologic factor
  • monoclonal antibody
  • adult
  • adult respiratory distress syndrome
  • aged
  • antiinflammatory activity
  • Article
  • artificial ventilation
  • clinical outcome
  • cohort analysis
  • complement inhibition
  • continuous infusion
  • coronavirus disease 2019
  • disease severity
  • exploratory research
  • extracellular trap
  • follow up
  • hemolysis
  • human
  • hyperinflammation
  • inflammation
  • interstitial pneumonia
  • lactate dehydrogenase blood level
  • lung function
  • neutrophil count
  • pneumonia
  • priority journal
  • protein blood level
  • tissue injury
  • Betacoronavirus
  • blood
  • complement activation
  • complication
  • Coronavirus infection
  • drug effect
  • female
  • gene expression
  • genetics
  • immunology
  • male
  • metabolism
  • middle aged
  • neutrophil
  • pandemic
  • pathogenicity
  • severity of illness index
  • virology
  • virus pneumonia
  • Antibodies, Monoclonal, Humanized
  • C-Reactive Protein
  • Cohort Studies
  • Complement Activation
  • Complement C3
  • Complement C5
  • Complement Inactivating Agents
  • Coronavirus Infections
  • Extracellular Traps
  • Female
  • Gene Expression
  • Humans
  • Immunologic Factors
  • Interleukin-6
  • Male
  • Middle Aged
  • Neutrophils
  • Pandemics
  • Peptides, Cyclic
  • Pneumonia, Viral
  • Respiratory Distress Syndrome, Adult
  • Severity of Illness Index


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