Journal of thrombosis and haemostasis : JTH · 2025
Protective effects of factor XI inhibition by abelacimab in a baboon model of live Staphylococcus aureus sepsis.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Silasi Robert, Keshari Ravi S, Abe Tomohiro, Byrum Stephanie D, Regmi Girija, Lupu Cristina, Georgescu Constantin, Simmons Joe H, Shamanaev Aleksandr, Moellmer Samantha A, Puy Cristina, Shatzel Joseph J, Province Dennis, Edmondson Rick D, Mackintosh Samuel G, Avaritt Nathan L, Bloomfield Dan, Gailani David, Tackett Alan J, McCarty Owen J T, Lupu Florea
Аннотация
BACKGROUND: Sepsis remains a major clinical challenge characterized by dysregulated immune response, coagulation abnormalities, and multiorgan failure, leading to high morbidity and mortality.
OBJECTIVES: This study investigated the therapeutic potential of abelacimab, a monoclonal antibody targeting the plasma zymogen factor (F)XI, in a new baboon model of Staphylococcus aureus sepsis.
METHODS: Healthy Papio anubis baboons were randomly assigned to control or abelacimab treatment groups. Both groups (n = 6, each) were intravenously infused with a median lethal (LD50) dose of live S aureus. The treatment group was administered abelacimab 30 minutes after the onset of bacterial infusion. Hematologic, coagulation, inflammatory, and organ function parameters were monitored for 7 days or until the animal exhibited signs of irreversible organ failure. Proteomic analysis was conducted to elucidate the underlying mechanisms by which abelacimab offered protection.
RESULTS: All 6 abelacimab-treated baboons survived until the 7-day endpoint, while 3 out of 6 untreated controls succumbed to sepsis within 102 hours. Abelacimab significantly attenuated sepsis-induced coagulopathy without signs of bleeding, as evidenced by biochemical tests and pathology analysis. Treated animals exhibited decreased proinflammatory cytokines, diminished neutrophil activation, and preservation of endothelial integrity, collectively conferring robust protection against organ damage. Proteomic analysis revealed that abelacimab modulated pathways related to coagulation, inflammation, and tissue injury, contributing to improved survival outcomes.
CONCLUSION: FXI inhibition by abelacimab offers significant protection by attenuating activation of coagulation, reducing inflammation, and preventing organ failure. Targeting FXI may be a promising therapeutic strategy for managing sepsis by addressing multiple facets of its complex pathophysiology.
OBJECTIVES: This study investigated the therapeutic potential of abelacimab, a monoclonal antibody targeting the plasma zymogen factor (F)XI, in a new baboon model of Staphylococcus aureus sepsis.
METHODS: Healthy Papio anubis baboons were randomly assigned to control or abelacimab treatment groups. Both groups (n = 6, each) were intravenously infused with a median lethal (LD50) dose of live S aureus. The treatment group was administered abelacimab 30 minutes after the onset of bacterial infusion. Hematologic, coagulation, inflammatory, and organ function parameters were monitored for 7 days or until the animal exhibited signs of irreversible organ failure. Proteomic analysis was conducted to elucidate the underlying mechanisms by which abelacimab offered protection.
RESULTS: All 6 abelacimab-treated baboons survived until the 7-day endpoint, while 3 out of 6 untreated controls succumbed to sepsis within 102 hours. Abelacimab significantly attenuated sepsis-induced coagulopathy without signs of bleeding, as evidenced by biochemical tests and pathology analysis. Treated animals exhibited decreased proinflammatory cytokines, diminished neutrophil activation, and preservation of endothelial integrity, collectively conferring robust protection against organ damage. Proteomic analysis revealed that abelacimab modulated pathways related to coagulation, inflammation, and tissue injury, contributing to improved survival outcomes.
CONCLUSION: FXI inhibition by abelacimab offers significant protection by attenuating activation of coagulation, reducing inflammation, and preventing organ failure. Targeting FXI may be a promising therapeutic strategy for managing sepsis by addressing multiple facets of its complex pathophysiology.