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.
Subscribe to Journal
Get full journal access for 1 year
only 4,10 € per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Structures for Neo-2/15 monomer and its ternary complex with mouse IL-2Rβγc have been deposited in the Protein Data Bank with accession numbers 6DG6 and 6DG5, respectively. Diffraction images have been deposited in the SBGrid Data Bank with accession numbers 587 and 588, respectively, and validation reports are included in the Supplementary Information. Other data and materials are available upon request from the corresponding authors.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We thank B. Nordstrom, J. Nordstrom, P. Barrier and J. Barrier for the IPD Fund (Budget Number: 68-0341); CONACyT SNI (Mexico), CONACyT postdoctoral fellowship (Mexico) and IPD translational research program to D.-A.S.; NIH MSTP grant T32 GM007266 to S.Y.; JDRF (2-SRA-2016-236-Q-R) to U.Y.U.; la Caixa Fellowship (la Caixa Banking Foundation, Barcelona, Spain) to A.Q.-R.; FCT Portugal Ph.D. studentship to C.L.-A.; European Research Council (ERC StG, grant agreement 676832), FCT Investigator (IF/00624/2015), and the Royal Society (UF110046 and URF\R\180019) to G.J.L.B.; Marie Curie International Outgoing Fellowship (FP7-PEOPLE-2011-IOF 298976) to E.M.; Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship to C.D.W.; Washington Research Foundation to B.D.W.; NIH grant R35GM122543 to F.P.-A.; Mentored Clinical Scientist Development Award 1K08DK114563-01, and the American Gastroenterological Association Research Scholars Award to M.D.; NIH-RO1-AI51321, NIH-RO1-AI51321, Mathers Foundation, Younger Endowed Chair, and Howard Hughes Medical Institute to K.C.G.; and Howard Hughes Medical Institute and Michelson Medical Research Foundation to D.B. See Supplementary Information for extended acknowledgements.
Nature thanks Y. Jones, W. Schief and the other anonymous reviewer(s) for their contribution to the peer review of this work.