Studies on factor VIII toward a new therapeutic for hemophilia A

抄録

Factor VIII (FVIII) is an essential glycoprotein cofactor that accelerates the generation of factor Xa (FXa) by factor IXa (FIXa). FVIII is transformed into its active form, FVIIIa, after limited proteolytic cleavages by thrombin and FXa at the site of bleeding. My early research, using monoclonal antibodies, recombinant/synthetic polypeptides and anhydro-proteins, identified critical FVIII binding regions for von Willebrand factor (VWF), phosphatidylserine, thrombin, FXa, FIXa, APC and plasmin. The studies led to the generation of a humanized bispecific antibody to FIX(a) and FX as a new therapeutic for hemophilia A patients with and without FVIII inhibitor. The antibody, now termed emicizumab, mimics FVIIIa cofactor function by arranging FIXa and FX in a spatially suitable position, thereby accelerating FIXa-catalyzed FX activation. Phase 1 studies in healthy volunteers and in patients with hemophilia A were performed in Japan. Bleeding rates were remarkably reduced dose-dependently by weekly subcutaneous injection of the antibody irrespective of the presence FVIII inhibitor. The efficacy and tolerability and safety were further confirmed by international phase 3 studies in a total of 400 participants. Emicizumab prophylaxis has now become one of the important therapeutic options for hemophilia A with and without inhibitors