Molecular Characterization and Functional Activity of an IL-15 Antagonist MutIL-15/Fc Human Fusion Protein

Yang, Xiaoyi; Kallarakal, Abraham T.; Saptharishi, Nirmala; Jiang, Hengguang; Yang, Zhiwen; Xie, Yueqing; Mitra, Gautam; Zheng, Xin Xiao; Strom, Terry B.; Soman, Gopalan

doi:10.1021/mp300513j

Cited by 3 publications

(1 citation statement)

References 42 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…). Binding of Fc‐fusion drugs to human soluble and cellular FcγRs has been reported by others ; however, these studies did not evaluate all the canonical FcγR and cell types.…”

Section: Discussionmentioning

confidence: 95%

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

Levin

Lagassé

Burch

et al. 2017

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

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) that 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 Although 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 with the hFIX-treated group. Additionally, differences in plasma cytokine levels and in vitro CD4 T-cell responses suggest that whereas 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.

show abstract

“…). Binding of Fc‐fusion drugs to human soluble and cellular FcγRs has been reported by others ; however, these studies did not evaluate all the canonical FcγR and cell types.…”

Section: Discussionmentioning

confidence: 95%