Abstract Number: PB0821
Meeting: ISTH 2020 Congress
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.
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 October 26, 2020.
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