RESUMEN
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.
Asunto(s)
Betacoronavirus/patogenicidad , Complemento C3/antagonistas & inhibidores , Complemento C5/antagonistas & inhibidores , Inactivadores del Complemento/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , COVID-19 , Estudios de Cohortes , Activación de Complemento/efectos de los fármacos , Complemento C3/genética , Complemento C3/inmunología , Complemento C5/genética , Complemento C5/inmunología , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Trampas Extracelulares/efectos de los fármacos , Femenino , Expresión Génica , Humanos , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/virología , Pandemias , Péptidos Cíclicos/uso terapéutico , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , Neumonía Viral/virología , Síndrome de Dificultad Respiratoria/complicaciones , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2 , Índice de Severidad de la EnfermedadRESUMEN
Ahead of Print article withdrawn by publisher.
Age-related macular degeneration is a leading cause of blindness in the elderly population worldwide. While treatments exist for the exudative (wet) form of the disease, no therapies have thus far been approved for geographic atrophy (GA), the advanced form of the non-exudative (dry) type of age-related macular degeneration. Abnormalities in the immune system are thought to be one of the major causes of GA. Pegcetacoplan is a treatment previously approved for treatment of paroxysmal nocturnal hematuria (a rare disorder that occurs when an individual's immune system attacks their own red blood cells). This article shows that when administered as an injection into the eye, pegcetacoplan shows promise as a future treatment option for patients with GA.