Protective Effects of FXI Inhibition by Abelacimab in a Baboon Model of live Staphylococcus aureus Sepsis

ABSTRACT: Sepsis remains a major clinical challenge characterized by dysregulated immune response, coagulation abnormalities, and multi-organ failure, leading to high morbidity and mortality. This study investigates the therapeutic potential of Abelacimab, a novel monoclonal antibody targeting the plasma zymogen coagulation fFactor XI/XIa (FXI/XIa), in a baboon model of live Staphylococcus aureus sepsis. Healthy Papio anubis baboons were randomly assigned to either a control or a treatment group receiving Abelacimab. Both groups (n=6, each) were intravenously infused with a LD50 dose of live S. aureus. The treatment group was administered Abelacimab, 30 minutes after bacterial infusion. Hematologic, coagulation, inflammatory, and organ function parameters were monitored for 7 days or until the animals exhibited signs of irreversible organ failure. Proteomic analysis was conducted to elucidate the underlying mechanisms by which Abelacimab offered protection. All six Abelacimab-treated baboons survived to the 7-day endpoint, while three out of six untreated controls succumbed to sepsis within 102 hours. Abelacimab significantly attenuated sepsis-induced consumptive coagulopathy, as evidenced by coagulation and fibrinolysis markers. Treated animals showed decreased levels of pro-inflammatory cytokines, reduced neutrophil activation, and preservation of endothelial integrity, leading to reduced organ damage. Proteomic analysis revealed that Abelacimab modulated pathways related to coagulation, inflammation, and tissue injury, contributing to improved survival outcomes. We found that FXI/XIa inhibition by Abelacimab offers significant protection in a model of live S. aureus sepsis by attenuating activation of coagulation factors, reducing inflammation, and preventing organ failure. These findings suggest that targeting FXI may be a promising therapeutic strategy for managing sepsis, addressing multiple facets of its complex pathophysiology.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Papio Anubis (ncbitaxon:9555)

SUBMITTER: Florea Lupu  

PROVIDER: MSV000095928 | MassIVE |

SECONDARY ACCESSION(S): PXD056090

REPOSITORIES: MassIVE