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

Abstract

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.