Journal article
De novo design of potent and selective mimics of IL-2 and IL-15
Nature (London), Vol.565(7738), pp.186-191
2019
DOI: 10.1038/s41586-018-0830-7
PMID: 30626941
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 βγ
heterodimer (IL-2Rβγ
) 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-2Rβγ
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-2Rβγ
, 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.
Details
- Title: Subtitle
- De novo design of potent and selective mimics of IL-2 and IL-15
- Creators
- Daniel-Adriano Silva - University of WashingtonShawn Yu - University of WashingtonUmut Y Ulge - University of WashingtonJamie B Spangler - Stanford UniversityKevin M Jude - Stanford UniversityCarlos Labão-Almeida - University of LisbonLestat R Ali - Massachusetts General HospitalAlfredo Quijano-Rubio - University of WashingtonMikel Ruterbusch - University of WashingtonIsabel Leung - Fred Hutch Cancer CenterTamara Biary - Massachusetts General HospitalStephanie J Crowley - Harvard UniversityEnrique Marcos - University of WashingtonCarl D Walkey - University of WashingtonBrian D Weitzner - University of WashingtonFátima Pardo-Avila - Stanford UniversityJavier Castellanos - University of WashingtonLauren Carter - University of WashingtonLance Stewart - University of WashingtonStanley R Riddell - Fred Hutch Cancer CenterMarion Pepper - University of WashingtonGonçalo J L Bernardes - University of CambridgeMichael Dougan - Harvard UniversityK Christopher Garcia - Stanford UniversityDavid Baker - University of Washington
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.565(7738), pp.186-191
- DOI
- 10.1038/s41586-018-0830-7
- PMID
- 30626941
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Publisher
- Springer Nature
- Grant note
- R01 AI051321 / NIAID NIH HHS T32 GM007266 / NIGMS NIH HHS R37 AI051321 / NIAID NIH HHS S10 OD021832 / NIH HHS Howard Hughes Medical Institute R35 GM122543 / NIGMS NIH HHS
- Language
- English
- Date published
- 2019
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985178661102771
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