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

Read about our new study comparing C3 inhibition with C5 blockade in COVID19: our early clinical findings offer important insight into the differential mechanistic basis of C3 & C5 inhibition and support a broader therapeutic profile of AMY101 in COVID-19.

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.

Author and source information

Authors: Mastellos DC, Pires da Silva BGP, Fonseca BAL, Fonseca NP, Martins MA, Mastaglio S, Ruggeri A, Sironi M, Radermacher P, Chrysanthopoulou A, Skendros P, Ritis K, Manfra I, Iacobelli S, Huber-Lang M, Nilsson B, Yancopoulou D, Connolly S, Garlanda C, Ciceri F, Risitano A, Calado RT, Lambris JD (2020). Complement C3 vs C5 inhibition in severe COVID-19: early clinical findings reveal differential biological efficacy. Clinical Immunology.