Abstract Number: OC 14.1
Meeting: ISTH 2021 Congress
Background: The major complication of FVIII replacement therapy in hemophilia A patients is the development of inhibitory anti-FVIII antibodies. Using FVIII-KO mice, we have shown that the transplacental delivery of the Fcγ1-fused A2 and C2 FVIII domains during gestation induces partial immune tolerance to therapeutic FVIII in the progeny.
Aims: To determine whether the transplacental delivery of whole FVIII induces complete FVIII tolerance.
Methods: To developed molecules able to capture maternal FVIII and deliver it to the fetuses, we cloned three monovalent IgG (FabFc) that crosslink FVIII and the neonatal Fc receptor (FcRn) and are specific for the A2 (BOIIB2), C1 (KM33) or C2 (BO2C11) FVIII domains. Their capacity to cross the placenta and deliver human B domain-deleted FVIII to fetuses was tested in pregnant FVIII-KO or double FVIII/VWF-KO mice and quantified by ELISA.
Results: FVIII injected alone did not reach the fetuses’ circulation. Co-incubation of FVIII with BO2C11 and KM33 FabFcs allowed the transplacental delivery of FVIII in FVIII-KO mice. FVIII concentrations in fetuses’ plasma ranged between 0,04 and 0,4 nM. Conversely, BOIIB2 FabFc failed to deliver FVIII from both FVIII-KO and double FVIII/VWF-KO mothers to fetuses.
Conclusions: While maternal FVIII does not spontaneously cross the placenta, monovalent anti-FVIII IgG deliver maternal FVIII transplacentally in an epitope-dependent manner. The inability of an A2 domain-specific FabFc to deliver FVIII to fetuses is not due to the binding of FVIII to VWF in the maternal circulation. In future experiments, the use of a deglycosylated N297A KM33 FabFc variant, that does not bind FcgR, will reveal the importance of FcgR binding in facilitation/blocking of the transplacental delivery of maternal FVIII. Further, the use of novel model of transgenic mice expressing human FVIII will indicate whether the continuous delivery of maternal FVIII during pregnancy yields sufficient amounts of FVIII in fetuses to induce FVIII-specific immune tolerance.
To cite this abstract in AMA style:Mimoun A, Bou Jaoudeh M, Peyron I, Daventure V, Delignat S, Reyes Ruiz A, Christophe O, Lenting P, Denis C, Lacroix-Desmazes S. Transplacental Delivery of Maternal FVIII for Induction of FVIII-specific Immune Tolerance [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/transplacental-delivery-of-maternal-fviii-for-induction-of-fviii-specific-immune-tolerance/. Accessed December 10, 2023.
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