Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy.
Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy.
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DOI：
10.1016/j.clim.2020.108598
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Lambris JD
中科院分区：
文献类型：
--
作者：
Mastellos DC;Pires da Silva BGP;Fonseca BAL;Fonseca NP;Auxiliadora-Martins M;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 ES;Garlanda C;Ciceri F;Risitano AM;Calado RT;Lambris JD
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。失调的补体激活可能会加剧尼古丁驱动的过度炎症、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感染的有害后果的候选药物已经获得了吸引力。阻断终末补体效应子（C5、C5 a或C5 aR 1）是否可能引起与C3水平上游干预相似的结果仍有争议。在这里，我们比较了C5靶向单克隆抗体依库珠单抗与基于坎普他汀的C3靶向候选药物AMY-101在小型独立队列的严重COVID-19患者中的疗效。我们的探索性研究表明，治疗性补体抑制可消除COVID-19过度炎症。C3和C5抑制剂都能引起强烈的抗炎反应，表现为C-反应蛋白和IL-6水平的急剧下降、肺功能的显著改善以及SARS-CoV-2相关急性呼吸窘迫综合征（ARDS）的消退。C3抑制通过减弱C3 a和sC 5 b-9的产生并防止FB消耗，在COVID-19患者中提供了更广泛的治疗控制。这种更广泛的抑制特征与中性粒细胞计数更稳健的下降、中性粒细胞胞外陷阱（NET）释放减弱、血清LDH下降更快和淋巴细胞恢复更显著相关。这些早期临床结果为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的更广泛致病性参与。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治疗药物。补体激活失调是严重COVID-19病理生理学的基础补体抑制消除COVID-19过度炎症，导致SARS-CoV-2相关ARDS消退C3与C5抑制的不同特征表明C3抑制对NET驱动的血栓炎症有更广泛的影响
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. Deregulated complement activation underpins the pathophysiology of severe COVID-19 Complement inhibition abrogates COVID-19 hyper-inflammation leading to resolution of SARS-CoV-2-associated ARDS Divergent profiles of C3 vs C5 inhibition point to a broader impact of C3 inhibition on NET-driven thromboinflammation
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DOI：
10.1007/s005990050029
发表时间：
1998-06-01
期刊：
INTERNATIONAL JOURNAL OF CLINICAL & LABORATORY RESEARCH
影响因子：
--
作者：
Crockard, AD;Boylan, MT;Hawkins, SA
通讯作者：
Hawkins, SA
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
影响因子：
64.8
作者：
Carvelli, Julien;Demaria, Olivier;Vivier, Eric
通讯作者：
Vivier, Eric
影响因子：
100.3
作者：
Chen, Zeyu;John Wherry, E.
通讯作者：
John Wherry, E.
影响因子：
158.5
作者：
Ackermann, Maximilian;Verleden, Stijn E.;Jonigk, Danny
通讯作者：
Jonigk, Danny