An engineered Treg selective immunocytokine induces sustained immune modulation in a preclinical model of hemophilia A.

BACKGROUND

The development of inhibitory antibodies (inhibitors) is a serious complication in the treatment of hemophilia A with clotting factor (F)VIII replacement therapy. Inhibitor formation critically depends on T cell help and modulation by regulatory T cells (Tregs).

OBJECTIVES

In this study, we evaluated the F5111 immunocytokine (IC), a single-chain fusion between the human interleukin (IL)-2 cytokine and an IL-2 antibody that biases cytokine activity toward cells with high IL-2 receptor (IL-2R)α expression, leading to extended IL-2 half-life and selective expansion of Tregs.

METHODS

A transient F5111 IC administration regimen was applied to a hemophilia A murine model of FVIII replacement therapy. Inhibitory antibody development to FVIII was monitored longitudinally by Bethesda assay and ELISA.

RESULTS

F5111 IC failed to stimulate cell types that predominantly express the dimeric IL2Rβγ receptor complex such as effector T and natural killer cells. Potent and highly transient Treg expansion was associated with suppression of effector T cells and in vivo conversion into Tregs. When tested in the hemophilia A mouse model, F5111 IC completely prevented the formation of inhibitors against FVIII for up to 4 months, long after Treg numbers returned to baseline levels.

CONCLUSION

These results demonstrate that F5111 IC induces a superior and prolonged tolerogenic response compared with an unbiased control IC. Overall, this study presents a novel and effective strategy for preventing inhibitory antibodies that hinder the effectiveness of FVIII replacement therapy in hemophilia A.