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) can elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we have compared the clinical efficacy of the C5-targeting mAb eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe, mainly non-intubated 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 CRP and IL-6 levels, associated with marked lung function improvement and resolution of SARS-CoV-2-associated ARDS. C3 inhibition afforded broader therapeutic control in COVID19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile of anti-C3 treatment was associated with a more robust decline of neutrophil counts, a greater decline of median LDH levels and more prominent lymphocyte recovery within the first 7 days of treatment. These early clinical results offer important insight into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19. They point to a broader pathogenic involvement of C3-mediated pathways and set the stage for larger prospective trials that will benchmark these complement-targeting agents in COVID-19.
