OC 59.2 - Analyzing Concizumab mechanism of action by a Mathematical Modeling Approach

Background: Concizumab is a high affinity monoclonal antibody targeting TFPI that reduces bleeding in hemophilia. Concizumab binds the Kunitz-2 domain of TFPI and effectively blocks inhibition of FXa. TFPI inhibits coagulation through multiple reactions. Our mathematical models predict TFPI as a therapeutic target to recover thrombin generation in hemophilia and, therefore, can be used to systematically explore concizumab mechanisms.

Aims: To assess the plausibility and effects of multiple mechanisms of concizumab action on TFPI inhibition using mathematical models.

Methods: A single-compartment mathematical model was developed to estimate the steady-state concentrations of concizumab in blood. This model considered binding interactions between concizumab, TFPIα, and endothelium-bound TFPIβ. The binding reaction for concizumab to TFPIα was then added to a separate mathematical model of flow-mediated coagulation. The coagulation model simulates thrombin generation at an injury site represented by a patch of tissue factor (TF) exposed to flowing blood. Concentrations from the steady-state model were used as inputs to the coagulation model. TF densities, concentrations of concizumab, and binding rates were varied and the resulting simulated thrombin curves were analyzed.

Results: Concizumab enhanced simulated thrombin generation in hemophilia A at low tissue factor (TF) and to a lesser extent at high TF. Concizumab worked through multiple mechanisms: preventing inhibition of plasma and platelet-bound FXa and preventing inhibition of TF:VIIa by TFPI:FXa. The model also predicted that concizumab physically traps TFPIα to endothelium by binding TFPIβ with one arm and TFPIα with the other.

Conclusion(s): The model predicts that concizumab enhances thrombin generation in hemophilia A at low TF by cumulatively preventing TFPI inhibition at the (sub)endothelium, in plasma, and on platelet surfaces. In addition, concizumab binding to TFPIβ was predicted to result in trapping of TFPIα at the endothelium, thereby reducing plasma TFPIα.