MG1113, a specific anti–tissue factor pathway inhibitor antibody, rebalances the coagulation system and promotes hemostasis in hemophilia

Abstract

Background Replacement therapy is the most common treatment for reduction of bleeding and control of episodic bleeding in individuals with hemophilia. Despite the proven effectiveness of factor replacement therapy, repeated intravenous administration is a heavy burden to individuals with hemophilia. Objectives To reduce the burden, therapeutic agents that can be subcutaneously administered need to be developed, and an anti–tissue factor pathway inhibitor (TFPI) antibody may be a suitable candidate for this purpose. Methods MG1113 is an IgG4 monoclonal antibody that binds to Kunitz‐2 domain (KD2) of TFPI. To confirm the coagulation potential of MG1113, several tests were conducted using factor VIII (FVIII)‐ or IX (FIX)‐deficient plasma. For the ex vivo spiking test, platelet‐poor plasma samples from 14 individuals with hemophilia were spiked with MG1113. The in vivo efficacy was determined using blood loss tests, modified prothrombin time (mPT), and free TFPI quantification after intravenous or subcutaneous administration of MG1113 into hemophilia A (HA)‐induced rabbits. Results Radiographic crystallography demonstrated the specific binding site between MG1113 and KD2. In FVIII‐deficient plasma and the plasma of individuals with hemophilia, peak thrombin and endogenous thrombin levels were increased by MG1113 in a concentration‐dependent manner. Rotational thromboelastometry assay revealed that clotting time, clot formation time, and maximum clot firmness were normalized in MG1113‐treated blood of patients. Intravenous or subcutaneous injection of MG1113 into HA‐induced rabbits resulted in rebalancing of blood loss, mPT, and free TFPI levels. Conclusions These results indicate that subcutaneous administration of MG1113 neutralizes the function of TFPI and regulates bleeding in individuals with hemophilia.

Factor V east Texas variant causes bleeding in a three‐generation family

“…The restoration of thrombin generation with this single monoclonal antibody is consistent with a central role for the binding of the second Kunitz domain to the active site of FXa in the TFPIα anticoagulant activity producing bleeding in these patients, which may be mediated by its role in the inhibition of TF‐FVIIa 9 or prothrombinase 19 . In this regard, there are several humanized anti‐TFPI monoclonal antibodies directed against the second Kunitz domain presently in clinical trials for hemophilia as a non‐factor therapy for prophylaxis 25‐29 . It remains to be determined if these may hold promise as a prophylactic agent for severe spontaneous bleeding episodes in some patients with FV‐short 5 …”

“…19 In this regard, there are several humanized anti-TFPI monoclonal antibodies directed against the second Kunitz domain presently in clinical trials for hemophilia as a non-factor therapy for prophylaxis. [25][26][27][28][29] It remains to be determined if these may hold promise as a prophylactic agent for severe spontaneous bleeding episodes in some patients with FV-short. 5 Interestingly, in our pedigree, three affected individuals have reported delayed wound healing with one suffering from recurrent angular cheilitis that did not heal properly and persisted for more than a year.…”

Target‐mediated drug disposition modeling of an anti‐TFPI antibody (MG1113) in cynomolgus monkeys to predict human pharmacokinetics and pharmacodynamics

“…The in vitro studies demonstrated that MG1113 binds to free TFPI of humans, monkeys, and rabbits. Accordingly the in vivo efficacy (modified prothrombin time, activated partial thromboplastin time, and hemoglobin loss) was observed after the administration of MG1113 to the rabbit hemophilia model 12 . The TFPI inhibitor products (fucoidan and PF‐06741086) and Aptamer ARC19499 have been shown to block FXa inhibition by TFPI, restore hemostasis, and reduce blood loss in hemophilia A mice and hemophilia‐induced monkey models 13–15 .…”

“…Accordingly the in vivo efficacy (modified prothrombin time, activated partial thromboplastin time, and hemoglobin loss) was observed after the administration of MG1113 to the rabbit hemophilia model. 12 The TFPI inhibitor products (fucoidan and PF-06741086) and Aptamer ARC19499 have been shown to block FXa inhibition by TFPI, restore hemostasis, and reduce blood loss in hemophilia A mice and hemophilia-induced monkey models. [13][14][15] The in vitro and in vivo potency results of concizumab, an antibody with properties most similar to those of MG1113, have also been reported in hemophilia-induced rabbits.…”

Progress in the Development of Anti-tissue Factor Pathway Inhibitors for Haemophilia Management

“…MG1113 is humanised IgG4 monoclonal antibody that binds to the Kunitz-2 domain (K2) of TFPI. It has been shown in vitro to restore thrombin generation in animals deficient in FVIII or FIX with and without inhibitors ( 29 ). In the ex vivo experiments, spiking haemophilia plasmas with MG1113 increased thrombin generation in a concentration-dependent fashion.…”