[Basic research supporting discovery and lifecycle development of antibody therapeutics for hemophilia]

Hemophilia treatment has shifted from conventional intravenous coagulation factor replacement toward reconstruction of hemostatic balance using non-factor agents. Antibody therapeutics have changed the drug discovery concept in hemophilia because of their long half-life, subcutaneous administration, target specificity, and flexibility of molecular engineering. Antibody-based therapeutics for hemophilia can be broadly divided into two categories: FVIIIa-mimetic bispecific antibodies, which bridge activated factor IX and factor X to substitute for the cofactor function of activated factor VIII, and anti-tissue factor pathway inhibitor antibodies, which rebalance hemostasis by attenuating the physiological anticoagulant pathway. This review summarizes basic research supporting discovery and lifecycle development of antibody therapeutics for hemophilia, focusing on molecular design, cell-based coagulation, rebalancing therapy, thrombin generation assay, laboratory implementation, concomitant hemostatic agents, anti-drug antibodies, and remaining challenges in individualized treatment.