Electrostatic interactions between the C1 domain and NB33. (A) Electrostatic surface potential (blue, positive charge; red, negative charge) of the ET3i C1 domain (top) and NB33 Fab fragment (bottom) at ±10 kcal/(mol·e^–). (B) FVIII residue K2065/R2090/K2092/R2159 (sticks) docked onto an acidic patch formed by the NB33 V_H domain (surface). NB33 is colored based on the electrostatic surface potential, as in panel A. (C) The structure of the C1 domain bound to NB33. Charged residues in the epitope (C1 domain, orange) and paratope (NB33 V_L, light pink; NB33 V_H, dark purple) are depicted as spheres. (D) The proposed pipeline for the development of FVIII replacement therapeutics with reduced LRP1-mediated clearance and immunogenicity by targeting surface-exposed arginine and lysine residues.