Abstract Number: OC 48.2
Meeting: ISTH 2021 Congress
Background: Development of inhibitory anti-factor VIII (FVIII) antibodies after replacement therapy with FVIII is a serious problem in patients with hemophilia A (HA). The injection to pregnant mice of Fc-fused A2 and C2 FVIII domains leads to their transplacental delivery, induction of FVIII-specific regulatory T cells in the offspring and partial tolerance to exogenous therapeutic FVIII. We hypothesized that the transplacental delivery of the entire FVIII should confer complete immune tolerance.
Aims: Evaluate the transplacental delivery of rFVIIIFc in FVIII-KO mice.
Methods: Pregnant FVIII-KO female mice were injected with rFVIIIFc, rFVIIIY1680FFc (impaired binding to von Willebrand factor (VWF)), B domain-deleted FVIII, monoclonal human IgG or C2Fc. The amounts of FVIII, IgG and C2Fc were measured in fetuses’ plasma. 6-week old pups from treated mothers received therapeutic FVIII once a week for 5 weeks and inhibitory anti-FVIII IgG development was investigated.
Results: In contrast to rFVIII, rFVIIIFc crossed the placenta in a time and dose-dependent manner with ~7 ng/ml detected in fetuses’ plasma 4 hr after injection of 50 µg rFVIIIFc to the mothers. This amount was 300-fold lower than that of C2Fc measured in the plasma of fetuses from C2Fc-treated pregnant mice. The injection of rFVIIIY1680FFc yielded similar amounts of transcytosis to that of rFVIIIFc. The treatment of pregnant mice with 50 µg rFVIIIFc at gestation days E16, E17 and E18 failed to prevent the onset of FVIII inhibitors in the offspring.
Conclusions: rFVIIIFc is delivered through the placenta to lesser extents than IgG and C2Fc. The transplacental delivery of rFVIIIFc is not affected by its binding to VWF. The transferred amounts of rFVIIIFc do not induce immune tolerance to exogenous FVIII in the offspring. We are now studying the implication of the different domains of FVIII in the reduced transplacental delivery of rFVIIIFc.
To cite this abstract in AMA style:Reyes-Ruiz A, Delignat S, Mimoun A, Azam A, Lillicrap D, Lacroix-Desmazes S. Transplacental Delivery of Recombinant Fc-fused Factor VIII (rFVIIIFc) in FVIII-deficient Mice [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/transplacental-delivery-of-recombinant-fc-fused-factor-viii-rfviiifc-in-fviii-deficient-mice/. Accessed November 29, 2023.
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