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.

越来越多的临床证据表明补体是 COVID-19 免疫病理学的关键驱动因素。补体激活失调可能会加剧细胞因子驱动的过度炎症、血栓性微血管病和 NET 驱动的免疫血栓形成，从而导致多器官衰竭。补体疗法作为对抗 SARS-CoV-2 感染有害后果的候选药物已受到关注。末端补体效应器（C5、C5a 或 C5aR1）的阻断是否可能引起与 C3 水平的上游干预类似的结果仍有争议。在这里，我们比较了 C5 靶向单克隆抗体依库丽单抗与基于坎普他汀的 C3 靶向候选药物 AMY-101 在小型独立队列的重症 COVID-19 患者中的疗效。我们的探索性研究表明，治疗性补体抑制可以消除 COVID-19 的过度炎症。C3 和 C5 抑制剂均能引起强大的抗炎反应，表现为 C 反应蛋白和 IL-6 水平急剧下降、肺功能显着改善以及 SARS-CoV-2 相关急性呼吸窘迫综合征 (ARDS) 的缓解）。C3 抑制通过减弱 C3a 和 sC5b-9 的生成并防止 FB 消耗，为 COVID-19 患者提供了更广泛的治疗控制。这种更广泛的抑制谱与中性粒细胞计数更剧烈的下降、中性粒细胞胞外陷阱 (NET) 释放减弱、血清 LDH 下降更快以及淋巴细胞恢复更显着相关。这些早期临床结果为了解 COVID-19 中 C3 和 C5 抑制的差异机制基础和潜在生物学提供了重要见解，并指出 C3 介导的途径在血栓炎症中具有更广泛的致病作用。他们还支持在大型前瞻性试验中评估这些补体靶向药物作为 COVID-19 疗法的效果。