Abstract Number: PB0856
Meeting: ISTH 2020 Congress
Background: One-third of severe hemophilia A patients develop (f)actor VIII alloinhibitory antibodies conferring the most significant treatment-related complication. From a protein therapeutic standpoint, FVIII is considered highly immunogenic. Further, compared to other coagulation factors, FVIII autoantibody formation is the highest. Collectively, this raises the possibility that the biochemical nature of FVIII is distinct from an immune perspective. The homology of FV and FVIII would suggest that these proteins may illicit a similar immune response; yet this is not supported by the very low prevalence of FV autoantibodies.
Aims: To evaluate the immune response to homologous B-domain deleted forms of human FVIII and FV proteins in mouse models.
Methods: B-domainless FVIII or FV (58% sequence homology) protein were administered via tail vein injection at a dose of 5 µg/mouse weekly for 5 weeks, then every-other-week in 3 murine models on the C57BL/6 background. The models were: wild type (WT) mice; WT-mice treated with an antisense oligonucleotide to knock down FV to < 5% of normal (FV-ASO); and transgenic mice with no plasma FV and low platelet FV (plt-FV). Anti-factor IgG concentration and Bethesda assays of functional inhibition were measured in longitudinal plasma samples.
Results: In WT and FV-ASO mice, the FV immune response was undetectable/low (< 10 BU), while the FVIII immune response was robust (>200 BU). The FV immune response remained low in plt-FV mice; surprisingly, the FVIII immune response was ~10-fold higher compared to WT and FV-ASO mice infused with FVIII (>2000 BU; Fig. 1).
Conclusions: To our knowledge, these data are the first to compare the immune response to FVIII relative to its homologous protein, FV, and demonstrate a markedly increased murine immune response to FVIII relative to FV. This preliminary data also support plasma FV may be relevant to FVIII immunogenicity, suggesting shared FV/VIII epitopes may be particularly important for FVIII tolerance.
To cite this abstract in AMA style:Sauer ML, Wilhelm AR, Davidson RJ, George LA, Camire RM. A Comparative Analysis of the Immune Response to Homologous Coagulation Factors V and VIII [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/a-comparative-analysis-of-the-immune-response-to-homologous-coagulation-factors-v-and-viii/. Accessed October 26, 2020.
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