July 27, 2023: Kenneth Childers, Department of Chemistry, Western Washington University

Structural basis for inhibition of coagulation factor VIII visualized by cryo-EM
Coagulation factor VIII (FVIII) promotes hemostasis by binding to activated factor IX on activated platelet surfaces to form the intrinsic tenase complex. Patients with congenital hemophilia A have a dysfunctional FVIII, leading to uncontrolled bleeding events. The formation of antibody inhibitors against FVIII occurs in approximately 30% of congenital hemophilia A patients receiving FVIII replacement therapy, as well as in cases of acquired hemophilia A where otherwise healthy individuals spontaneously generate antibodies, significantly complicating treatment. By identifying the FVIII amino acids which bind to pathogenic antibody inhibitors, FVIII replacement therapeutics can be engineered with reduced immunogenicity and a prolonged circulatory half-life. Using recent advances in cryogenic electron microscopy (cryo-EM), we have determined structures of FVIII bound to three patient-derived antibodies, including the first structure of FVIII bound to an anti-A2 domain antibody. These structures provide a mechanistic rationale for inhibiting FVIII function, such as increasing FVIII clearances rates and disrupting formation of the intrinsic tenase complex. Our structural analysis delineates the amino acids which promote an immune response to FVIII and will be critical in the design of next- generation FVIII replacement therapeutics.