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Nature. 2019 Jan;565(7738):186-191. doi: 10.1038/s41586-018-0830-7. Epub 2019 Jan 9.

De novo design of potent and selective mimics of IL-2 and IL-15.

Author information

1
Institute for Protein Design, University of Washington, Seattle, WA, USA. dadriano@uw.edu.
2
Department of Biochemistry, University of Washington, Seattle, WA, USA. dadriano@uw.edu.
3
Institute for Protein Design, University of Washington, Seattle, WA, USA.
4
Department of Bioengineering, University of Washington, Seattle, WA, USA.
5
Departments of Biomedical Engineering and Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
6
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
7
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
8
Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
9
Department of Biochemistry, University of Washington, Seattle, WA, USA.
10
Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
11
Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA.
12
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
13
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
14
Department of Chemistry, University of Cambridge, Cambridge, UK.
15
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.
16
Howard Hughes Medical Institute, Chevy Chase, MD, USA. kcgarcia@stanford.edu.
17
Institute for Protein Design, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
18
Department of Biochemistry, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
19
Howard Hughes Medical Institute, Chevy Chase, MD, USA. dabaker@uw.edu.

Abstract

We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor βγc heterodimer (IL-2Rβγc) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rβγc with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rβγc, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.

PMID:
30626941
DOI:
10.1038/s41586-018-0830-7

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