Modulating immunogenicity of Factor IX by fusion to an immunoglobulin Fc domain: a study using hemophilia B mouse model.

Modulating immunogenicity of Factor IX by fusion to an immunoglobulin Fc domain: a study using hemophilia B mouse model.

J Thromb Haemost. 2017 Feb 06;:

Authors: Levin D, Lagassé HA, Burch E, Strome S, Tan S, Jiang H, Sauna ZE, Golding B

Abstract
BACKGROUND: Fc-fusion is a platform technology used to increase the circulating half-life of protein and peptide therapeutics. However, there are potential immunological consequences with this approach, such as changes in the molecule's immunogenicity as well as possible interactions with a repertoire of Fc-receptors (FcR) which can modulate immune responses.
OBJECTIVES/METHODS: Using a mouse hemophilia B (HB) model, we compared the immune responses to infusions of recombinant human Factor IX (hFIX) and hFIX fused to mouse IgG2a-Fc (hFIX-mFc). The mFc was employed to allow species-specific Fc-FcγR interactions.
RESULTS: While treatment with hFIX-mFc altered the early development of anti-FIX IgG, no significant differences in anti-FIX antibody titers were observed at the end of the treatment regimen (5 weeks) or upon anamnestic response (5 months). However, treatment with hFIX-mFc elicited higher FIX-neutralizing antibody levels and resulted in reduced IgE titers compared to the hFIX-treated group. Additionally, differences in plasma cytokine levels and in vitro CD4(+) T cell responses suggest that while hFIX treatment triggered a Th2-biased immune response; hFIX-mFc treatment induced Th1-biased CD4(+) T cells. We also show that hFIX-mFc bound to soluble FcγRs and engaged with FcγRs on different cell types, which may impact antigen presentation.
CONCLUSIONS: These studies provide a model system to study how Fc-fusion proteins may affect immune mechanisms. We used this model to demonstrate a plausible mechanism by which Fc-fusion may modulate the IgE response to hFIX. This model may be appropriate for investigating the rare but severe IgE-mediated anaphylaxis reaction to hFIX infusions in HB patients. This article is protected by copyright. All rights reserved.

PMID: 28166609 [PubMed - as supplied by publisher]

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