Activation and immune processing mechanisms of FVIII-KB013bv compared with BDD-FVIII. (A) BDD-FVIII binds VWF. Following activation by thrombin, FVIII is activated to FVIIIa and dissociates from VWF. Alternately, the complex circulates and interacts with the cell surface of APCs. During this interaction, VWF remains on the APC surface while FVIII is endocytosed. FVIII peptides are processed by the APC and subsequently presented to CD4⁺ T cells. (B) FVIII-KB013bv, an FVIII-nanobody fusion protein, replaces B-domain residues with 2 copies of KB-VWF-013. KB-VWF-013 recognizes the FVIII-binding D′D3 region and binds VWF with 25-fold higher affinity compared with BDD-FVIII. Activation by thrombin cleavage liberates the nanobody insert, which likely remains attached to VWF. FVIII activity and VWF activity are unaffected. Upon interaction of the complex with APCs, FVIII does not dissociate and remains at the cell surface, reducing internalization. Lack of endocytosis leads to decreased presentation of FVIII peptides by the major histocompatibility complex class II, reducing immunogenicity.