Abstract Number: PB0821
Meeting: ISTH 2020 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Basic
Background: Concizumab is a humanized, anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in phase 3 clinical development as a once-daily, subcutaneous prophylaxis for hemophilia A or B with or without inhibitors. Activated protein C and antithrombin are two independent negative regulators of coagulation, acting downstream and independent of TFPI.
Aims: To assess whether concizumab binding to endothelial cell-surface-associated TFPI affects protein C activation by thrombin or antithrombin inhibition of thrombin.
Methods: The affinity of concizumab for cell-surface-associated TFPI was assessed in a competition ELISA using human umbilical vein endothelial cells (HUVECs). The effect of concizumab on thrombin-mediated protein C activation on the HUVECs was measured at different protein C and thrombin concentrations in the absence or presence of excess concizumab (50 or 250 µg/mL). The effect of concizumab on antithrombin-mediated thrombin inhibition was measured at different antithrombin concentrations using protein C as thrombin substrate.
Results: Concizumab bound TFPI expressed on HUVECs with a KD of 0.42 nM (95% CI: 0.33−0.52 nM) and at 50 and 250 µg/mL concizumab (0.3 and 1.7 µM, respectively), all TFPI was saturated. Concizumab (50 or 250 µg/mL) did not affect thrombin-mediated protein C activation (Figure 1A and 1B). An inhibitory anti-thrombomodulin antibody completely blocked the reaction, confirming thrombomodulin-dependency of the assay. No effect of concizumab on antithrombin inhibition of thrombin was observed (Figure 1C).
Conclusions: Concizumab did not affect protein C activation or antithrombin activity in an in vitro set-up, consistent with its specificity for TFPI. The data suggest that the function of these downstream major coagulation inhibitors may be maintained in patients with hemophilia receiving concizumab prophylaxis.
[Figure 1. Downstream effects of concizumab binding to TFPI on protein C activation and antithrombin activity.]
To cite this abstract in AMA style:
Kjalke M, Heibroch Petersen H, Hilden I. In vitro Effect of Concizumab on Protein C Activation and Antithrombin Activity [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/in-vitro-effect-of-concizumab-on-protein-c-activation-and-antithrombin-activity/. Accessed January 18, 2021.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/in-vitro-effect-of-concizumab-on-protein-c-activation-and-antithrombin-activity/