Figure 2.

Immunological profile of efanesoctocog alfa. A classical immune response to a T-cell-dependent extracellular antigen, such as therapeutic Factor VIII (FVIII), involves: i) the uptake of the antigen by antigen-presenting cells; ii) the processing of the antigen and presentation of antigen-derived peptides on MHC class II molecules to antigen-specific naïve CD4⁺ T cells; iii) the activation of the T cells; iv) a cross-talk between the activated T cells and naïve B cells that express antigen-specific B-cell receptors; and v) the differentiation of the B cells into antibody-secreting cells. The figure depicts the proposed interactions of the different moieties of efanesoctocog alfa (Efa) (i.e., FVIII, crystallizable fragments [Fc], XTEN polypeptides, and von Willebrand Factor [vWF] D’D3 domains) with the different phases of the immune response. Green arrow symbols indicate a probable effect in mellowing down immunogenicity; orange arrows indicate a possible effect on immunogenicity. Thus, cellular uptake may be reduced by the virtue of the presence of the XTEN polypeptides and the vWF D’D3 domains. XTEN polypeptides are not presented on MHCII molecules to T cells. FVIII and Fc fragments contain Tregitopes that may reduce, at least in part, the immunogenicity of the molecule, particularly if D’D3 were found to also contain Tregitopes. The XTEN polypeptides and the D’D3 domains may also reduce the binding of FVIII to the B-cell receptor of FVIII-specific naïve and memory B cells, thus reducing the T/B-cell cross-talk. IgG: immunoglobulin G.