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

Dimitrios C. Mastellos, Bruno G.P. Pires da Silva, Benedito A.L. Fonseca, Natasha P. Fonseca, Maria Auxiliadora-Martins, Sara Mastaglio, Annalisa Ruggeri, Marina Sironi, Peter Radermacher, Akrivi Chrysanthopoulou, Panagiotis Skendros, Konstantinos Ritis, Ilenia Manfra, Simona Iacobelli, Markus Huber-Lang, Bo Nilsson, Despina Yancopoulou, E. Sander Connolly, Cecilia Garlanda, Fabio CiceriAntonio M. Risitano, Rodrigo T. Calado, John 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.

Original languageEnglish
Article number108598
JournalClinical Immunology
Publication statusPublished - Nov 2020


  • AMY-101
  • Biomarkers
  • C3 inhibition
  • C5 blockade
  • COVID-19
  • Drug efficacy
  • Eculizumab
  • Thromboinflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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