A103-05 Angiopoietin 2 Inhibition Preserves Hemodynamics in a Swine Model of Sepsis

Abstract Rationale Despite decades of research, sepsis lacks targeted therapeutics that prevent organ injury and improve survival. Angiopoietin 2 (Angpt2) is a systemically circulating protein, released from the endothelium in response to inflammation, which disrupts vascular integrity via antagonism of the TEK receptor tyrosine kinase 2 (Tie2). Sepsis-induced elevation of Angpt2 is associated, in a concentration-dependent manner, with the development of end organ dysfunction and loss of hemodynamic homeostasis. These findings suggest that Angpt2 inhibition may have therapeutic potential. We hypothesized that Angpt2 inhibition by a monoclonal antibody (mAb) would improve hemodynamics during sepsis. Methods In a swine model of sepsis (n = 3), lipopolysaccharide (LPS; 0.5 - 1.5 µg/kg) was intravenously administered at T0, followed by a dose-escalating infusion of a therapeutic Angpt2 mAb (LY3127804; Eli Lilly; total dose 7 mg/kg) at T8 h. Hemodynamics and blood sampling for the measurement of Angpt2 were performed every 2 hours for 24 hours. Plasma Angpt2 (free and total) was quantified by ELISA and cytokines by a porcine Luminex assay. Pre-Angpt2 mAb data (T3 - T8 h) were compared to post-mAb data (T9 - T24 h) by Welch’s t-test and mean arterial pressure (MAP) vs time was analyzed by linear regression. Results All animals mounted an inflammatory response to LPS as evidenced by increased plasma cytokines (e.g., TNF, IL-6). Plasma Angpt2 concentrations increased over time in response to LPS. Following the administration of Angpt2 Mab, free Angpt2 dramatically declined (12,524 ± 2,884 vs 585 ± 153.8 pg/mL mean ± SD, p = 0.02) and remained lower than pre-treatment concentrations (Figure). Following mAb administration, heart rate declined (101 ± 5.9 vs 76 ± 10.4 mean ± SD, p = 0.03) and urine output increased (29.7 ± 4.62 vs 89.3 ± 43.1 mL/h mean ± SD, p = 0.14). The MAP stabilized over time post-mAb when compared to pre-mAb (-1.3 vs -4.8 slope, p = 0.0004). Conclusion Angpt2 inhibition with a therapeutic mAb in septic swine produced sustained Angpt2 suppression which translated to hemodynamic improvement and increased urine output. These results provide preclinical support for Angpt2 inhibition that may be beneficial in stabilizing sepsis-induced hemodynamic disruption. Further studies are warranted to confirm these findings and evaluate the clinical potential of Angpt2 as a therapeutic target in sepsis. This abstract is funded by: R35GM136312