Factor VIII antibody immune complexes modulate the humoral response to factor VIII in an epitope-dependent manner.

Introduction: Soluble antigens complexed with immunoglobulin G (IgG) antibodies can induce robust adaptive immune responses and in animal models of disease. Factor VIII immune complexes (FVIII-ICs) have been detected in individuals with hemophilia A and severe von Willebrand disease following FVIII infusions. Yet, it is unclear if and how FVIII-ICs affect antibody development over time.

Methods: In this study, we analyzed internalization of FVIII complexed with epitope-mapped FVIII-specific IgG monoclonal antibodies (MAbs) by murine bone marrow-derived dendritic cells (BMDCs) and antibody development in hemophilia A (FVIII) mice injected with FVIII-IC over time.

Results: FVIII complexed with 2-116 (A1 domain MAb), 2-113 (A3 domain MAb), and I55 (C2 domain MAb) significantly increased FVIII uptake by BMDC but only FVIII/2-116 enhanced antibody titers in FVIII mice compared to FVIII alone. FVIII/4A4 (A2 domain MAb) showed similar FVIII uptake by BMDC to that of isolated FVIII yet significantly increased antibody titers when injected in FVIII mice. Enhanced antibody responses observed with FVIII/2-116 and FVIII/4A4 complexes were abrogated in the absence of the FVIII carrier protein von Willebrand factor.

Conclusion: These findings suggest that a subset of FVIII-IC modulates the humoral response to FVIII in an epitope-dependent manner, which may provide insight into the antibody response observed in some patients with hemophilia A.