Background: The major complication of factor VIII (FVIII)-based therapy in hemophilia A patients is the development of inhibitory anti-FVIII antibodies. Using FVIII-deficient mice, we have shown that the transplacental delivery of the Fcγ1-fused A2 and C2 domains of FVIII during gestation induces immune tolerance to therapeutic FVIII in the progeny. Babies from A2-Fc/C2-Fc-treated mothers developed regulatory T cells and were partially protected, albeit not completely, from the development of FVIII inhibitors.

Aims: To determine whether the transplacental delivery of whole FVIII induces complete FVIII tolerance, we developed molecules able to capture circulating maternal FVIII and deliver it to the fetuses.

Methods: We cloned Fc-fused molecules that crosslink human FVIII and the neonatal Fc receptor (FcRn): two monovalent FabFcs (V_LC_k/V_HCH1CH2CH3-linker-CH2CH3) derived from the specific human anti-C2 BO2C11 and anti-A2 BOIIB2 IgG4k monoclonal antibodies, and a D’D3-Fc derived from human von Willebrand factor. The molecules produced in CHO cells were validated for binding to FVIII and FcRn by ELISA and surface plasmon resonance. Their capacity to cross the placenta and deliver B domain-deleted FVIII (BDD) to fetuses was tested in pregnant FVIII-KO mice.

Results: BO2C11-FabFc, BOIIB2-FabFc and D’D3-Fc bound to FVIII and to FcRn with affinities of 0.4, 0.3 and 5 nM, and 11.6, 5.22, and 0.69 nM, respectively. The molecules were transplacentally delivered. The delivery of BDD-FVIII remains to be confirmed.

Conclusions: We generated 3 recombinant proteins able to bind FVIII and FcRn, and demonstrated FcRn-dependent transcytosis. Confirmation of the transplacental delivery of exogenously administered BDD-FVIII to fetuses is pending. We are developing a model of transgenic mice expressing human FVIII. This model will be instrumental to bring the proof-of-concept that maternal FVIII can be delivered through the placenta to the offspring. The consequences on the induction of FVIII-specific immune tolerance will be investigated.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/transplacental-delivery-of-maternal-factor-viii-for-induction-of-immune-tolerance-to-therapeutic-factor-viii/