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

2019Journal article Restricted access
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dc.contributor.authorSilva, Daniel-Adriano
dc.contributor.authorYu, Shawn
dc.contributor.authorUlge, Umut Y.
dc.contributor.authorSpangler, Jamie B.
dc.contributor.authorJude, Kevin M.
dc.contributor.authorLabão-Almeida, Carlos
dc.contributor.authorAli, Lestat R.
dc.contributor.authorQuijano-Rubio, Alfredo
dc.contributor.authorRuterbusch, Mikel
dc.contributor.authorLeung, Isabel
dc.contributor.authorBiary, Tamara
dc.contributor.authorCrowley, Stephanie J.
dc.contributor.authorMarcos, Enrique
dc.contributor.authorWalkey, Carl D.
dc.contributor.authorWeitzner, Brian D.
dc.contributor.authorPardo-Avila, Fátima
dc.contributor.authorCastellanos, Javier
dc.contributor.authorCarter, Lauren
dc.contributor.authorStewart, Lance
dc.contributor.authorRiddell, Stanley R.
dc.contributor.authorPepper, Marion
dc.contributor.authorBernardes, Gonçalo J. L.
dc.contributor.authorDougan, Michael
dc.contributor.authorGarcia, K. Christopher
dc.contributor.authorBaker, David
dc.date.accessioned2022-04-12T14:09:06Z
dc.date.available2022-04-12T14:09:06Z
dc.date.issued2019
dc.description© 2019 Springer Nature limited. All rights reserved.pt_PT
dc.description.abstractWe 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.pt_PT
dc.description.sponsorshipWe 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNature. 2019 Jan;565(7738):186-191pt_PT
dc.identifier.doi10.1038/s41586-018-0830-7pt_PT
dc.identifier.eissn1476-4687
dc.identifier.issn0028-0836
dc.identifier.urihttp://hdl.handle.net/10451/52309
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationA Minimal-Tag Bioorthogonal Labelling Approach to Protein Uptake, Traffic and Delivery
dc.relationModulation and targeting of calcium channels with ligand-drug conjugates for cancer therapy
dc.relation.publisherversionhttps://www.nature.com/pt_PT
dc.titleDe novo design of potent and selective mimics of IL-2 and IL-15pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleA Minimal-Tag Bioorthogonal Labelling Approach to Protein Uptake, Traffic and Delivery
oaire.awardTitleModulation and targeting of calcium channels with ligand-drug conjugates for cancer therapy
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/676832/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00624%2F2015%2FCP1287%2FCT0002/PT
oaire.citation.endPage191pt_PT
oaire.citation.issue7738pt_PT
oaire.citation.startPage186pt_PT
oaire.citation.titleNaturept_PT
oaire.citation.volume565pt_PT
oaire.fundingStreamH2020
oaire.fundingStreamInvestigador FCT
person.familyNameLabão-Almeida
person.familyNameBernardes
person.givenNameCarlos
person.givenNameGonçalo
person.identifier.ciencia-id2713-8EF2-5EFB
person.identifier.orcid0000-0002-7797-3797
person.identifier.orcid0000-0001-6594-8917
person.identifier.scopus-author-id14046757500
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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