Zobraziť v EDS

Directed disruption of IL2 aggregation and receptor binding sites produces designer biologics with enhanced specificity and improved production capacity

Uložené v:
Podrobná bibliografia
Názov: Directed disruption of IL2 aggregation and receptor binding sites produces designer biologics with enhanced specificity and improved production capacity
Autori: Amy Dashwood, Ntombizodwa Makuyana, Rob van der Kant, Arman Ghodsinia, Alvaro R. Hernandez, Stephanie Lienart, Oliver Burton, James Dooley, Magda Ali, Lubna Kouser, Francisco Naranjo, Matthew G. Holt, Frederic Rousseau, Joost Schymkowitz, Adrian Liston
Prispievatelia: DSpace at Cambridge pro (8.1)
Zdroj: Comput Struct Biotechnol J
Computational and Structural Biotechnology Journal, Vol 27, Iss, Pp 1112-1123 (2025)
Informácie o vydavateľovi: Elsevier BV, 2025.
Rok vydania: 2025
Predmety: Biochemistry & Molecular Biology, 3101 Biochemistry and cell biology, Science & Technology, COMPLEX, PREDICTION, 0103 Numerical and Computational Mathematics, 4601 Applied computing, SEQUENCE, HUMAN IL-2, Biotechnology & Applied Microbiology, ALPHA-RECEPTOR, T-CELLS, Interleukin-2, INTERLEUKIN-2 THERAPY, Protein engineering, PROTEIN AGGREGATION, Life Sciences & Biomedicine, Cytokine, IN-VIVO, TP248.13-248.65, 0802 Computation Theory and Mathematics, Biotechnology, Research Article
Popis: The pleotropic nature of interleukin-2 (IL2) has allowed it to be used as both a pro-inflammatory and anti-inflammatory therapeutic agent, through promotion of regulatory T cell (Treg) responses via the trimeric IL2RABG receptor or promotion of CD8 T cell responses via the dimeric IL2RBG receptor, respectively. However, the utility of IL2 as a treatment is limited by this same pleiotropy, and protein engineering to bias specificity towards either Treg or CD8 T cell lineage often requires a trade-off in protein production or total bioactivity. Here we use SolubiS and dTANGO, computational algorithm-based methods, to predict mutations within the IL2 structure to improve protein production yield in muteins with altered cellular selectivity, to generate combined muteins with elevated therapeutic potential. The design and testing process identified the V106R (murine) / V91R (human) mutation as a Treg-enhancing mutein, creating a cation repulsion to inhibit primary binding to IL2RB, with a post-IL2RA confirmational shift enabling secondary IL2RB binding, and hence allowing the trimeric receptor complex to form. In human IL2, additional N90R T131R aggregation-protecting mutations could improve protein yield of the V91R mutation. The approach also generated novel CD8 T cell-promoting mutations. Y59K created a cation-cation repulsion with IL2RA, while Q30W enhanced CD8 T cell activity through potential π-stacking enhancing binding to IL2RB, with the combination highly stimulatory for CD8 T cells. For human IL2, Y45K (homolog to murine Y59K) coupled with E62K prevented IL2RA binding, however it required the aggregation-protecting mutations of N90R T131R to rescue production. These muteins, designed with both cellular specificity and protein production features, have potential as both biological tools and therapeutics.
Druh dokumentu: Article
Other literature type
Popis súboru: application/pdf
Jazyk: English
ISSN: 2001-0370
DOI: 10.1016/j.csbj.2025.03.002
Prístupová URL adresa: https://pubmed.ncbi.nlm.nih.gov/40190571
https://doaj.org/article/bbf5a2197aa04d7885455a6e9ab2ddf3
Rights: CC BY NC ND
Prístupové číslo: edsair.doi.dedup.....efaeda788c8597534dcab4bfd22f9ba4
Databáza: OpenAIRE
FullText Text:
  Availability: 0
CustomLinks:
  – Url: https://explore.openaire.eu/search/publication?articleId=doi_dedup___%3A%3Aefaeda788c8597534dcab4bfd22f9ba4
    Name: EDS - OpenAIRE (s4221598)
    Category: fullText
    Text: View record at OpenAIRE
  – Url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=pmc&term=2001-0370[TA]+AND+1112[PG]+AND+2025[PDAT]
    Name: FREE - PubMed Central (ISSN based link)
    Category: fullText
    Text: Full Text
    Icon: https://imageserver.ebscohost.com/NetImages/iconPdf.gif
    MouseOverText: Check this PubMed for the article full text.
  – Url: https://resolver.ebscohost.com/openurl?sid=EBSCO:edsair&genre=article&issn=20010370&ISBN=&volume=27&issue=&date=20250101&spage=1112&pages=1112-1123&title=Computational and Structural Biotechnology Journal&atitle=Directed%20disruption%20of%20IL2%20aggregation%20and%20receptor%20binding%20sites%20produces%20designer%20biologics%20with%20enhanced%20specificity%20and%20improved%20production%20capacity&aulast=Amy%20Dashwood&id=DOI:10.1016/j.csbj.2025.03.002
    Name: Full Text Finder
    Category: fullText
    Text: Full Text Finder
    Icon: https://imageserver.ebscohost.com/branding/images/FTF.gif
    MouseOverText: Full Text Finder
  – Url: https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=EBSCO&SrcAuth=EBSCO&DestApp=WOS&ServiceName=TransferToWoS&DestLinkType=GeneralSearchSummary&Func=Links&author=Dashwood%20A
    Name: ISI
    Category: fullText
    Text: Nájsť tento článok vo Web of Science
    Icon: https://imagesrvr.epnet.com/ls/20docs.gif
    MouseOverText: Nájsť tento článok vo Web of Science
Header DbId: edsair
DbLabel: OpenAIRE
An: edsair.doi.dedup.....efaeda788c8597534dcab4bfd22f9ba4
RelevancyScore: 1015
AccessLevel: 3
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 1014.736328125
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Directed disruption of IL2 aggregation and receptor binding sites produces designer biologics with enhanced specificity and improved production capacity
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Amy+Dashwood%22">Amy Dashwood</searchLink><br /><searchLink fieldCode="AR" term="%22Ntombizodwa+Makuyana%22">Ntombizodwa Makuyana</searchLink><br /><searchLink fieldCode="AR" term="%22Rob+van+der+Kant%22">Rob van der Kant</searchLink><br /><searchLink fieldCode="AR" term="%22Arman+Ghodsinia%22">Arman Ghodsinia</searchLink><br /><searchLink fieldCode="AR" term="%22Alvaro+R%2E+Hernandez%22">Alvaro R. Hernandez</searchLink><br /><searchLink fieldCode="AR" term="%22Stephanie+Lienart%22">Stephanie Lienart</searchLink><br /><searchLink fieldCode="AR" term="%22Oliver+Burton%22">Oliver Burton</searchLink><br /><searchLink fieldCode="AR" term="%22James+Dooley%22">James Dooley</searchLink><br /><searchLink fieldCode="AR" term="%22Magda+Ali%22">Magda Ali</searchLink><br /><searchLink fieldCode="AR" term="%22Lubna+Kouser%22">Lubna Kouser</searchLink><br /><searchLink fieldCode="AR" term="%22Francisco+Naranjo%22">Francisco Naranjo</searchLink><br /><searchLink fieldCode="AR" term="%22Matthew+G%2E+Holt%22">Matthew G. Holt</searchLink><br /><searchLink fieldCode="AR" term="%22Frederic+Rousseau%22">Frederic Rousseau</searchLink><br /><searchLink fieldCode="AR" term="%22Joost+Schymkowitz%22">Joost Schymkowitz</searchLink><br /><searchLink fieldCode="AR" term="%22Adrian+Liston%22">Adrian Liston</searchLink>
– Name: Author
  Label: Contributors
  Group: Au
  Data: DSpace at Cambridge pro (8.1)
– Name: TitleSource
  Label: Source
  Group: Src
  Data: Comput Struct Biotechnol J<br />Computational and Structural Biotechnology Journal, Vol 27, Iss, Pp 1112-1123 (2025)
– Name: Publisher
  Label: Publisher Information
  Group: PubInfo
  Data: Elsevier BV, 2025.
– Name: DatePubCY
  Label: Publication Year
  Group: Date
  Data: 2025
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Biochemistry+%26+Molecular+Biology%22">Biochemistry & Molecular Biology</searchLink><br /><searchLink fieldCode="DE" term="%223101+Biochemistry+and+cell+biology%22">3101 Biochemistry and cell biology</searchLink><br /><searchLink fieldCode="DE" term="%22Science+%26+Technology%22">Science & Technology</searchLink><br /><searchLink fieldCode="DE" term="%22COMPLEX%22">COMPLEX</searchLink><br /><searchLink fieldCode="DE" term="%22PREDICTION%22">PREDICTION</searchLink><br /><searchLink fieldCode="DE" term="%220103+Numerical+and+Computational+Mathematics%22">0103 Numerical and Computational Mathematics</searchLink><br /><searchLink fieldCode="DE" term="%224601+Applied+computing%22">4601 Applied computing</searchLink><br /><searchLink fieldCode="DE" term="%22SEQUENCE%22">SEQUENCE</searchLink><br /><searchLink fieldCode="DE" term="%22HUMAN+IL-2%22">HUMAN IL-2</searchLink><br /><searchLink fieldCode="DE" term="%22Biotechnology+%26+Applied+Microbiology%22">Biotechnology & Applied Microbiology</searchLink><br /><searchLink fieldCode="DE" term="%22ALPHA-RECEPTOR%22">ALPHA-RECEPTOR</searchLink><br /><searchLink fieldCode="DE" term="%22T-CELLS%22">T-CELLS</searchLink><br /><searchLink fieldCode="DE" term="%22Interleukin-2%22">Interleukin-2</searchLink><br /><searchLink fieldCode="DE" term="%22INTERLEUKIN-2+THERAPY%22">INTERLEUKIN-2 THERAPY</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+engineering%22">Protein engineering</searchLink><br /><searchLink fieldCode="DE" term="%22PROTEIN+AGGREGATION%22">PROTEIN AGGREGATION</searchLink><br /><searchLink fieldCode="DE" term="%22Life+Sciences+%26+Biomedicine%22">Life Sciences & Biomedicine</searchLink><br /><searchLink fieldCode="DE" term="%22Cytokine%22">Cytokine</searchLink><br /><searchLink fieldCode="DE" term="%22IN-VIVO%22">IN-VIVO</searchLink><br /><searchLink fieldCode="DE" term="%22TP248%2E13-248%2E65%22">TP248.13-248.65</searchLink><br /><searchLink fieldCode="DE" term="%220802+Computation+Theory+and+Mathematics%22">0802 Computation Theory and Mathematics</searchLink><br /><searchLink fieldCode="DE" term="%22Biotechnology%22">Biotechnology</searchLink><br /><searchLink fieldCode="DE" term="%22Research+Article%22">Research Article</searchLink>
– Name: Abstract
  Label: Description
  Group: Ab
  Data: The pleotropic nature of interleukin-2 (IL2) has allowed it to be used as both a pro-inflammatory and anti-inflammatory therapeutic agent, through promotion of regulatory T cell (Treg) responses via the trimeric IL2RABG receptor or promotion of CD8 T cell responses via the dimeric IL2RBG receptor, respectively. However, the utility of IL2 as a treatment is limited by this same pleiotropy, and protein engineering to bias specificity towards either Treg or CD8 T cell lineage often requires a trade-off in protein production or total bioactivity. Here we use SolubiS and dTANGO, computational algorithm-based methods, to predict mutations within the IL2 structure to improve protein production yield in muteins with altered cellular selectivity, to generate combined muteins with elevated therapeutic potential. The design and testing process identified the V106R (murine) / V91R (human) mutation as a Treg-enhancing mutein, creating a cation repulsion to inhibit primary binding to IL2RB, with a post-IL2RA confirmational shift enabling secondary IL2RB binding, and hence allowing the trimeric receptor complex to form. In human IL2, additional N90R T131R aggregation-protecting mutations could improve protein yield of the V91R mutation. The approach also generated novel CD8 T cell-promoting mutations. Y59K created a cation-cation repulsion with IL2RA, while Q30W enhanced CD8 T cell activity through potential π-stacking enhancing binding to IL2RB, with the combination highly stimulatory for CD8 T cells. For human IL2, Y45K (homolog to murine Y59K) coupled with E62K prevented IL2RA binding, however it required the aggregation-protecting mutations of N90R T131R to rescue production. These muteins, designed with both cellular specificity and protein production features, have potential as both biological tools and therapeutics.
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: Article<br />Other literature type
– Name: Format
  Label: File Description
  Group: SrcInfo
  Data: application/pdf
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 2001-0370
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1016/j.csbj.2025.03.002
– Name: URL
  Label: Access URL
  Group: URL
  Data: <link linkTarget="URL" linkTerm="https://pubmed.ncbi.nlm.nih.gov/40190571" linkWindow="_blank">https://pubmed.ncbi.nlm.nih.gov/40190571</link><br /><link linkTarget="URL" linkTerm="https://doaj.org/article/bbf5a2197aa04d7885455a6e9ab2ddf3" linkWindow="_blank">https://doaj.org/article/bbf5a2197aa04d7885455a6e9ab2ddf3</link>
– Name: Copyright
  Label: Rights
  Group: Cpyrght
  Data: CC BY NC ND
– Name: AN
  Label: Accession Number
  Group: ID
  Data: edsair.doi.dedup.....efaeda788c8597534dcab4bfd22f9ba4
PLink https://erproxy.cvtisr.sk/sfx/access?url=https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edsair&AN=edsair.doi.dedup.....efaeda788c8597534dcab4bfd22f9ba4
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1016/j.csbj.2025.03.002
    Languages:
      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 12
        StartPage: 1112
    Subjects:
      – SubjectFull: Biochemistry & Molecular Biology
        Type: general
      – SubjectFull: 3101 Biochemistry and cell biology
        Type: general
      – SubjectFull: Science & Technology
        Type: general
      – SubjectFull: COMPLEX
        Type: general
      – SubjectFull: PREDICTION
        Type: general
      – SubjectFull: 0103 Numerical and Computational Mathematics
        Type: general
      – SubjectFull: 4601 Applied computing
        Type: general
      – SubjectFull: SEQUENCE
        Type: general
      – SubjectFull: HUMAN IL-2
        Type: general
      – SubjectFull: Biotechnology & Applied Microbiology
        Type: general
      – SubjectFull: ALPHA-RECEPTOR
        Type: general
      – SubjectFull: T-CELLS
        Type: general
      – SubjectFull: Interleukin-2
        Type: general
      – SubjectFull: INTERLEUKIN-2 THERAPY
        Type: general
      – SubjectFull: Protein engineering
        Type: general
      – SubjectFull: PROTEIN AGGREGATION
        Type: general
      – SubjectFull: Life Sciences & Biomedicine
        Type: general
      – SubjectFull: Cytokine
        Type: general
      – SubjectFull: IN-VIVO
        Type: general
      – SubjectFull: TP248.13-248.65
        Type: general
      – SubjectFull: 0802 Computation Theory and Mathematics
        Type: general
      – SubjectFull: Biotechnology
        Type: general
      – SubjectFull: Research Article
        Type: general
    Titles:
      – TitleFull: Directed disruption of IL2 aggregation and receptor binding sites produces designer biologics with enhanced specificity and improved production capacity
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Amy Dashwood
      – PersonEntity:
          Name:
            NameFull: Ntombizodwa Makuyana
      – PersonEntity:
          Name:
            NameFull: Rob van der Kant
      – PersonEntity:
          Name:
            NameFull: Arman Ghodsinia
      – PersonEntity:
          Name:
            NameFull: Alvaro R. Hernandez
      – PersonEntity:
          Name:
            NameFull: Stephanie Lienart
      – PersonEntity:
          Name:
            NameFull: Oliver Burton
      – PersonEntity:
          Name:
            NameFull: James Dooley
      – PersonEntity:
          Name:
            NameFull: Magda Ali
      – PersonEntity:
          Name:
            NameFull: Lubna Kouser
      – PersonEntity:
          Name:
            NameFull: Francisco Naranjo
      – PersonEntity:
          Name:
            NameFull: Matthew G. Holt
      – PersonEntity:
          Name:
            NameFull: Frederic Rousseau
      – PersonEntity:
          Name:
            NameFull: Joost Schymkowitz
      – PersonEntity:
          Name:
            NameFull: Adrian Liston
      – PersonEntity:
          Name:
            NameFull: DSpace at Cambridge pro (8.1)
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 01
              Type: published
              Y: 2025
          Identifiers:
            – Type: issn-print
              Value: 20010370
            – Type: issn-locals
              Value: edsair
            – Type: issn-locals
              Value: edsairFT
          Numbering:
            – Type: volume
              Value: 27
          Titles:
            – TitleFull: Computational and Structural Biotechnology Journal
              Type: main
ResultId 1