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A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism

Abstract

Interleukin-2 (IL-2) has been shown to suppress immune pathologies by preferentially expanding regulatory T cells (Tregs). However, this therapy has been limited by off-target complications due to pathogenic cell expansion. Recent efforts have been focused on developing a more selective IL-2. It is well documented that certain anti-mouse IL-2 antibodies induce conformational changes that result in selective targeting of Tregs. We report the generation of a fully human anti-IL-2 antibody, F5111.2, that stabilizes IL-2 in a conformation that results in the preferential STAT5 phosphorylation of Tregs in vitro and selective expansion of Tregs in vivo. When complexed with human IL-2, F5111.2 induced remission of type 1 diabetes in the NOD mouse model, reduced disease severity in a model of experimental autoimmune encephalomyelitis and protected mice against xenogeneic graft-versus-host disease. These results suggest that IL-2–F5111.2 may provide an immunotherapy to treat autoimmune diseases and graft-versus-host disease.

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Fig. 1: Characterization of human anti-IL-2 antibodies with different receptor inhibition and human Treg pSTAT5 signaling profiles.
Fig. 2: Identification of a novel anti-human IL-2 antibody that inhibits effector T cell responses to IL-2 but does not block Treg pSTAT5.
Fig. 3: Antibody F5111.2 inhibits upregulation of IL-2-induced proteins in CD8+ T cells but not Tregs in vitro.
Fig. 4: The IL-2–F5111 complex structure reveals that the F5111 Fab obstructs the IL-2Rβ-binding site on IL-2.
Fig. 5: The F5111.2–hIL-2 complex preferentially increases Tregs in an in vivo NSG expansion model.
Fig. 6: The F5111.2–hIL-2 complex increases the Treg proportion and reinforces the Treg phenotype in inflamed pancreas leading to diabetes remission in NOD mice.

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Acknowledgements

We thank Pfizer for funding this study and participating in experiments and discussion, and the entire laboratory of J.A.B. and members of the laboratory of K.C.G. for support. In particular, we thank F. Van Gool and M. DuPage from the Bluestone laboratory for insightful discussions, D. Samuel from CTI-Pfizer for antibodies and protein preparation and UCSF Flow Core for its excellent technical assistance. We would also like to thank all of the healthy donors involved in this study.

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E.T., J.A.B., N.K.C. and I.J.R. designed the study; E.T., P.H.B., S.L.S., L.K.E., D.T.L. and C.R.H. performed experiments in vitro and in vivo with antibodies; M.P. performed experiments with MCMV; K.M.J. performed crystal structure analysis of F5111; L.L.L., K.C.G. and A.C. provided conceptual advice; E.T., J.A.B., N.K.C. and I.J.R. wrote the manuscript.

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Correspondence to Jeffrey A. Bluestone.

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CTI-Pfizer funded this study. E.T., P.H.B., L.K.E., N.K.C., J.A.B. and I.J.R. are co-inventors on a patent application filed by CTI-Pfizer and UCSF incorporating discoveries described in the manuscript.

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Trotta, E., Bessette, P.H., Silveria, S.L. et al. A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism. Nat Med 24, 1005–1014 (2018). https://doi.org/10.1038/s41591-018-0070-2

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