Abstract Number: PB0223
Meeting: ISTH 2020 Congress
Background: Up to 30 % of severe Hemophilia A patients develop inhibitory antibodies against therapeutic FVIII. Although several modified recombinant FVIII products are available, a deimmunized FVIII product which reduces the probability of inhibitor development has not yet been reported.
Aims: To develop FVIII with lower immunogenicity by reducing the number of FVIII-peptides presented on immune cells leading to a reduction of FVIII-specific naïve T cell maturation, and hence a reduction in the production of high-affinity inhibitory antibodies.
Methods: Using in silico tools, we screened the FVIII sequence and identified FVIII-unique peptides predicted to bind with high affinity to the MHC class II. Amino acid exchanges were incorporated in order to reduce MHC II presentation. Finally, 19 mutations were incorporated into the FVIII coding sequence without altering regions important for activity, folding and binding.
Results: Functional and structural analyses of this deimmunized FVIII variant revealed similarity to a non-modified FVIII reference and other registered rFVIII products. An in vitro DC-T cell assay was used to examine the immunogenicity of the deimmunized FVIII variant: DCs derived from healthy donors were co-cultured with autologous CD4+ T cells which were depleted for regulatory T cells in order to allow an anti-FVIII immune response. The DCs were primed with the non-modified and deimmunized FVIII products, and CD4+ T cell proliferation was measured. Using this assay, we demonstrated a significantly reduced immunogenicity of the deimmunized FVIII variant.
Conclusions: Here we present a deimmunized functional recombinant FVIII which was shown to be less immunogenic compared to a non-modified FVIII reference in an in vitro assay. When used as factor replacement therapy, this molecule has the potential to reduce the risk of inhibitor development in Hemophilia A patients.
To cite this abstract in AMA style:Winterling K, Martin W, De Groot AS, Daufenbach J, Schüttrumpf J, Kistner S. A Novel Coagulation Factor VIII with Reduced Immunogenicity [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/a-novel-coagulation-factor-viii-with-reduced-immunogenicity/. Accessed March 3, 2021.
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