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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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.

Author information

Author notes

  1. These authors jointly supervised this work: Natasha K. Crellin, Isaac J. Rondon, Jeffrey A. Bluestone.

Affiliations

  1. UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA

    • Eleonora Trotta
    • , Stephanie L. Silveria
    •  & Jeffrey A. Bluestone
  2. Centers for Therapeutic Innovation, Pfizer Inc., San Francisco, CA, USA

    • Paul H. Bessette
    • , Lauren K. Ely
    • , Natasha K. Crellin
    •  & Isaac J. Rondon
  3. Departments of Molecular & Cellular Physiology and Structural Biology, Stanford University, Stanford, CA, USA

    • Kevin M. Jude
    •  & K. Christopher Garcia
  4. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA

    • Kevin M. Jude
    •  & K. Christopher Garcia
  5. Department of Pediatric Immunology, Allergy and Rheumatology, University of Houston, Houston, TX, USA

    • Duy T. Le
  6. BioElectron Technology Corporation, Mountain View, CA, USA

    • Charles R. Holst
  7. Pandion Therapeutics, Cambridge, MA, USA

    • Anthony Coyle
  8. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA

    • Marc Potempa
    •  & Lewis L. Lanier
  9. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA

    • K. Christopher Garcia
  10. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA

    • Jeffrey A. Bluestone

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Contributions

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.

Competing interests

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.

Corresponding author

Correspondence to Jeffrey A. Bluestone.

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DOI

https://doi.org/10.1038/s41591-018-0070-2

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