Recombinant factor VIII Fc fusion protein drives regulatory macrophage polarization

• Published in: Blood advances 2018-11, Vol.2 (21), p.2904-2916
• Main Authors: Kis-Toth, Katalin, Rajani, Gaurav Manohar, Simpson, Allison, Henry, Kate L., Dumont, Jennifer, Peters, Robert T., Salas, Joe, Loh, Christine
• Format: Article
• Language: English
• Subjects: Cells, Cultured; Factor VIII - pharmacology; Factor VIII - therapeutic use; Gene Expression Regulation - drug effects; Hemophilia A - drug therapy; Hemophilia A - pathology; Humans; Immunobiology and Immunotherapy; Immunoglobulin Fc Fragments - pharmacology; Immunoglobulin Fc Fragments - therapeutic use; Leukocytes, Mononuclear - cytology; Macrophage Activation - drug effects; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Receptors, Fc - metabolism; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Signal Transduction - drug effects
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2018024497

The main complication of replacement therapy with factor in hemophilia A (HemA) is the formation of inhibitors (neutralizing anti–factor VIII [FVIII] antibodies) in ∼30% of severe HemA patients. Because these inhibitors render replacement FVIII treatment essentially ineffective, preventing or eliminating them is of top priority in disease management. The extended half-life recombinant FVIII Fc fusion protein (rFVIIIFc) is an approved therapy for HemA patients. In addition, it has been reported that rFVIIIFc may induce tolerance to FVIII more readily than FVIII alone in HemA patients that have developed inhibitors. Given that the immunoglobulin G1 Fc region has the potential to interact with immune cells expressing Fc receptors (FcRs) and thereby affect the immune response to rFVIII, we investigated how human macrophages, expressing both FcRs and receptors reported to bind FVIII, respond to rFVIIIFc. We show herein that rFVIIIFc, but not rFVIII, uniquely skews macrophages toward an alternatively activated regulatory phenotype. rFVIIIFc initiates signaling events that result in morphological changes, as well as a specific gene expression and metabolic profile that is characteristic of the regulatory type Mox/M2-like macrophages. Further, these changes are dependent on rFVIIIFc-FcR interactions. Our findings elucidate mechanisms of potential immunomodulatory properties of rFVIIIFc. •rFVIIIFc can induce macrophages to polarize to an alternatively activated Mox/M2 phenotype with antioxidant characteristics.•This polarization is dependent on intact rFVIIIFc–FcR interactions. [Display omitted]