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Linker minimization and characterization of Fc-fused interleukin-17A for increased in vivo half-life.

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Title: Linker minimization and characterization of Fc-fused interleukin-17A for increased in vivo half-life.
Authors: Wu, Qiu C1 (AUTHOR), Lee, Jungmin2 (AUTHOR), Swaminathan, Aishwarya3 (AUTHOR), Winward, Ashley3 (AUTHOR), Hwang, Yung3 (AUTHOR), Socolovsky, Merav3 (AUTHOR), Way, Jeffrey C4 (AUTHOR), Klein, Allon M1 (AUTHOR)
Source: PEDS: Protein Engineering, Design & Selection. 2025, Vol. 38, p1-11. 11p.
Subjects: Interleukin-17, Pharmacokinetics, Protein engineering, Cytokines, Chimeric proteins, Inflammation, Regeneration (Biology)
Abstract: Interleukin-17A (IL-17A) is a cytokine involved in pro-inflammatory responses and tissue regeneration, with potential therapeutic and research applications. However, its short serum half-life limits in vivo use. Here, we report the systematic design of fc-IL-17A fusion proteins for extended half-life. Through computational analysis of 25 design variants using AlphaFold, we found that IL-17A's native N-terminal unstructured region functions as a crucial natural linker that cannot be effectively replaced by artificial sequences. We therefore generated mouse and human fc-IL-17A variants using direct N-terminal fusion without additional linkers. The resulting proteins retain IL-17A's ability to stimulate IL-6 production and erythroid cell growth. Pharmacokinetic analysis confirms that the Fc fusion increases the serum half-life in mice from 1.5 to 13 hours post-subcutaneous injection. This enables tractable experimental use of IL-17A in vivo for studying its role in inflammation and tissue repair. We further perform pharmacokinetics and pharmacodynamics modeling and propose a dosing regimen with reduced frequency of injection for delivering comparable IL-17A activity. This work provides a valuable pharmacological tool for injectable delivery, enabling investigation of IL-17A's biological functions in homeostasis and disease and exploration of its therapeutic potential in tissue regeneration. [ABSTRACT FROM AUTHOR]
Copyright of PEDS: Protein Engineering, Design & Selection is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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DbLabel: Engineering Source
An: 191816618
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PubType: Academic Journal
PubTypeId: academicJournal
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  Label: Title
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  Data: Linker minimization and characterization of Fc-fused interleukin-17A for increased in vivo half-life.
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  Data: <searchLink fieldCode="AR" term="%22Wu%2C+Qiu+C%22">Wu, Qiu C</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lee%2C+Jungmin%22">Lee, Jungmin</searchLink><relatesTo>2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Swaminathan%2C+Aishwarya%22">Swaminathan, Aishwarya</searchLink><relatesTo>3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Winward%2C+Ashley%22">Winward, Ashley</searchLink><relatesTo>3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Hwang%2C+Yung%22">Hwang, Yung</searchLink><relatesTo>3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Socolovsky%2C+Merav%22">Socolovsky, Merav</searchLink><relatesTo>3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Way%2C+Jeffrey+C%22">Way, Jeffrey C</searchLink><relatesTo>4</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Klein%2C+Allon+M%22">Klein, Allon M</searchLink><relatesTo>1</relatesTo> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22PEDS%3A+Protein+Engineering%2C+Design+%26+Selection%22">PEDS: Protein Engineering, Design & Selection</searchLink>. 2025, Vol. 38, p1-11. 11p.
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  Data: <searchLink fieldCode="DE" term="%22Interleukin-17%22">Interleukin-17</searchLink><br /><searchLink fieldCode="DE" term="%22Pharmacokinetics%22">Pharmacokinetics</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+engineering%22">Protein engineering</searchLink><br /><searchLink fieldCode="DE" term="%22Cytokines%22">Cytokines</searchLink><br /><searchLink fieldCode="DE" term="%22Chimeric+proteins%22">Chimeric proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Inflammation%22">Inflammation</searchLink><br /><searchLink fieldCode="DE" term="%22Regeneration+%28Biology%29%22">Regeneration (Biology)</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Interleukin-17A (IL-17A) is a cytokine involved in pro-inflammatory responses and tissue regeneration, with potential therapeutic and research applications. However, its short serum half-life limits in vivo use. Here, we report the systematic design of fc-IL-17A fusion proteins for extended half-life. Through computational analysis of 25 design variants using AlphaFold, we found that IL-17A's native N-terminal unstructured region functions as a crucial natural linker that cannot be effectively replaced by artificial sequences. We therefore generated mouse and human fc-IL-17A variants using direct N-terminal fusion without additional linkers. The resulting proteins retain IL-17A's ability to stimulate IL-6 production and erythroid cell growth. Pharmacokinetic analysis confirms that the Fc fusion increases the serum half-life in mice from 1.5 to 13 hours post-subcutaneous injection. This enables tractable experimental use of IL-17A in vivo for studying its role in inflammation and tissue repair. We further perform pharmacokinetics and pharmacodynamics modeling and propose a dosing regimen with reduced frequency of injection for delivering comparable IL-17A activity. This work provides a valuable pharmacological tool for injectable delivery, enabling investigation of IL-17A's biological functions in homeostasis and disease and exploration of its therapeutic potential in tissue regeneration. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of PEDS: Protein Engineering, Design & Selection is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1093/protein/gzaf009
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      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 11
        StartPage: 1
    Subjects:
      – SubjectFull: Interleukin-17
        Type: general
      – SubjectFull: Pharmacokinetics
        Type: general
      – SubjectFull: Protein engineering
        Type: general
      – SubjectFull: Cytokines
        Type: general
      – SubjectFull: Chimeric proteins
        Type: general
      – SubjectFull: Inflammation
        Type: general
      – SubjectFull: Regeneration (Biology)
        Type: general
    Titles:
      – TitleFull: Linker minimization and characterization of Fc-fused interleukin-17A for increased in vivo half-life.
        Type: main
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          Name:
            NameFull: Wu, Qiu C
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            NameFull: Lee, Jungmin
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            NameFull: Swaminathan, Aishwarya
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            NameFull: Winward, Ashley
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            NameFull: Hwang, Yung
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            NameFull: Way, Jeffrey C
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            – D: 01
              M: 01
              Text: 2025
              Type: published
              Y: 2025
          Identifiers:
            – Type: issn-print
              Value: 17410126
          Numbering:
            – Type: volume
              Value: 38
          Titles:
            – TitleFull: PEDS: Protein Engineering, Design & Selection
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