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

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Mastellos, Dimitrios C. ^[1] ; Pires da Silva, Bruno G. P. ^[2] ; Fonseca, Benedito A. L. ^[3] ; Fonseca, Natasha P. ^[2] ; Auxiliadora-Martins, Maria ^[4] ; Mastaglio, Sara ^[5] ; Ruggeri, Annalisa ^[5] ; Sironi, Marina ^[6] ; Radermacher, Peter ^[7] ; Chrysanthopoulou, Akrivi ^{[8, 9]} ; Skendros, Panagiotis ^{[8, 9]} ; Ritis, Konstantinos ^{[8, 9]} ; Manfra, Ilenia ^[10] ; Iacobelli, Simona ^[11] ; Huber-Lang, Markus ^[12] ; Nilsson, Bo ^[13] ; Yancopoulou, Despina ^[14] ; Connolly, E. Sander ^[15] ; Garlanda, Cecilia ^{[16, 6]} ; Ciceri, Fabio ^{[17, 5]} ; Risitano, Antonio M. ^{[10, 18]} ; Calado, Rodrigo T. ^[2] ; Lambris, John D. ^[19]

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^[1] Natl Ctr Sci Res Demokritos, Athens - Greece

^[2] Univ Sao Paulo, Sch Med, Dept Med Imaging Hematol & Clin Oncol, Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Internal Med, Ribeirao Preto - Brazil

^[4] Univ Sao Paulo, Ribeirao Preto Sch Med, Intens Care Unit, Univ Hosp, Ribeirao Preto - Brazil

^[5] IRCCS San Raffaele Sci Inst, Hematol & Bone Marrow Transplantat Unit, Milan - Italy

^[6] IRCCS, Humanitas Clin & Res Ctr, Milan - Italy

^[7] Univ Hosp Ulm, Sekt Anasthesiol Pathophysiol & Verfahrensentwick, Ulm - Germany

^[8] Democritus Univ Thrace, Univ Hosp Alexandroupolis, Dept Internal Med 1, Alexandroupolis - Greece

^[9] Democritus Univ Thrace, Univ Hosp Alexandroupolis, Lab Mol Hematol, Alexandroupolis - Greece

^[10] AORN San Giuseppe Moscati, Hematol & Hematopoiet Stem Cell Transplantat Unit, Avellino - Italy

^[11] Univ Roma Tor Vergata, Dept Biol, Rome - Italy

^[12] Univ Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm - Germany

^[13] Uppsala Univ Hosp, Div Clin Immunol, Uppsala - Sweden

^[14] Amyndas Pharmaceut, Glifadha - Greece

^[15] Columbia Univ, Dept Neurol Surg, New York, NY - USA

^[16] Humanitas Univ, Milan - Italy

^[17] Univ Vita Salute San Raffaele, Milan - Italy

^[18] Federico II Univ Naples, Naples - Italy

^[19] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 - USA

• Tipo de documento: Artigo Científico
• Fonte: Clinical Immunology; v. 220, NOV 2020.
• Citações Web of Science: 4

Resumo

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. (AU)

• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs