Regulation of immune responses to therapeutic factor VIII by transplacental delivery of Fc-fused immunodominant factor VIII domains or peptides.

Patients with severe hemophilia A (HA) often develop undesired immune responses to therapeutic factor VIII (FVIII) that hamper replacement therapy with FVIII-derived products. The transplacental delivery of two Fc-fused FVIII domains in pregnant HA mice was shown to induce partial FVIII-specific immune tolerance in the offspring. Here, we evaluated whether the transplacental delivery of Fc-fused FVIII (rFVIIIFc) induces complete immune tolerance towards FVIII. rFVIIIFc injected to pregnant HA mice was poorly transferred to the fetal circulation and failed to confer tolerance to exogenous FVIII in the offspring. The poor transplacental delivery of rFVIIIFc was associated with the large size of the molecule and with the presence of positive patches at the surface of FVIII. It was however independent from the capacity of rFVIIIFc to bind Fcô€€€ receptor or von Willebrand factor in the maternal circulation. Conversely, the transplacental delivery of Fc-fused A2 and C2 immunodominant domains of FVIII, as well as of Fc-fused molecules containing seven different immunodominant FVIII-derived peptides decreased the levels of anti-FVIII antibodies following FVIII replacement therapy in the offspring. Our study paves the way towards the development of engineered Fc-fused molecules able to efficiently cross the placenta and confer potent and long-lasting immune tolerance to protein therapeutics.