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Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy.
Mastellos, Dimitrios C; 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.
  • Mastellos DC; National Center for Scientific Research 'Demokritos', Aghia Paraskevi, Athens, Greece.
  • Pires da Silva BGP; Department of Medical Imaging, Hematology and Clinical Oncology, University of São Paulo, Ribeirão Preto, School of Medicine, Brazil.
  • Fonseca BAL; Department of Internal Medicine, University of São Paulo, Ribeirão Preto School of Medicine, Brazil.
  • Fonseca NP; Department of Medical Imaging, Hematology and Clinical Oncology, University of São Paulo, Ribeirão Preto, School of Medicine, Brazil.
  • Auxiliadora-Martins M; Intensive Care Unit, University Hospital, University of São Paulo, Ribeirão Preto School of Medicine, Brazil.
  • Mastaglio S; Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Ruggeri A; Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Sironi M; Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy.
  • Radermacher P; Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, University Hospital of Ulm, Ulm, Germany.
  • Chrysanthopoulou A; First Department of Internal Medicine and Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
  • Skendros P; First Department of Internal Medicine and Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
  • Ritis K; First Department of Internal Medicine and Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
  • Manfra I; AORN San Giuseppe Moscati, Hematology and Hematopoietic Stem Cell Transplantation Unit, Avellino, Italy.
  • Iacobelli S; Department of Biology, University of Rome Tor Vergata, Rome, Italy.
  • Huber-Lang M; Institute for Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany.
  • Nilsson B; Division of Clinical Immunology, Uppsala University Hospital, Uppsala, Sweden.
  • Yancopoulou D; Amyndas Pharmaceuticals, Glyfada, Greece.
  • Connolly ES; Department of Neurological Surgery, Columbia University, New York, NY, USA.
  • Garlanda C; Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy; Humanitas University, Pieve Emanuele, Milan, Italy.
  • Ciceri F; Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; University Vita Salute San Raffaele, Milan, Italy.
  • Risitano AM; AORN San Giuseppe Moscati, Hematology and Hematopoietic Stem Cell Transplantation Unit, Avellino, Italy; Federico II University of Naples, Naples, Italy.
  • Calado RT; Department of Medical Imaging, Hematology and Clinical Oncology, University of São Paulo, Ribeirão Preto, School of Medicine, Brazil.
  • Lambris JD; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: lambris@pennmedicine.upenn.edu.
Clin Immunol ; 220: 108598, 2020 11.
Article in English | MEDLINE | ID: covidwho-778645
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Respiratory Distress Syndrome / Complement C3 / Complement C5 / Coronavirus Infections / Complement Inactivating Agents / Betacoronavirus / Immunologic Factors Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study Topics: Long Covid Language: English Journal: Clin Immunol Journal subject: Allergy and Immunology Year: 2020 Document Type: Article Affiliation country: J.clim.2020.108598

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Respiratory Distress Syndrome / Complement C3 / Complement C5 / Coronavirus Infections / Complement Inactivating Agents / Betacoronavirus / Immunologic Factors Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study Topics: Long Covid Language: English Journal: Clin Immunol Journal subject: Allergy and Immunology Year: 2020 Document Type: Article Affiliation country: J.clim.2020.108598