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Rational design of selective bispecific EPO-R/CD131 agonists.

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Title: Rational design of selective bispecific EPO-R/CD131 agonists.
Authors: Doiron, Kailyn E1 (AUTHOR), Way, Jeffrey C2 (AUTHOR), Silver, Pamela A2 (AUTHOR)
Source: PEDS: Protein Engineering, Design & Selection. 2025, Vol. 38, p1-15. 15p.
Subjects: Erythropoietin receptors, Bispecific antibodies, Erythropoietin, Progenitor cells, Structural models, STAT proteins, Cytokine receptors, Protein engineering
Abstract: Erythropoietin (EPO) suppresses apoptosis and promotes survival by signaling through EPO-R/EPO-R on hematopoietic progenitors or EPO-R/CD131 on non-hematopoietic cells. However, EPO signaling through EPO-R/CD131 is controversial and there is no solved structure of a complex. Here, we constructed a structural model of EPO-R/CD131 and designed several anti-EPO-R, anti-CD131 bispecific proteins that selectively activate EPO-R/CD131. Treatment with these fusion proteins is sufficient to activate STAT5 phosphorylation downstream of EPO-R/CD131 without engaging EPO-R/EPO-R. We demonstrated that proteins with a tandem scFv or bispecific antibody format activate EPO-R/CD131, in contrast to an equimolar mixture of the individual scFvs. Finally, we explored the effect of modifications to binding domain arrangement and linker length and found results consistent with our structural model of an EPO-R/CD131 complex. These findings highlight the utility of bispecific scaffolds in the development of cytokine receptor agonists and provide a foundation for the study of EPO-R/CD131 biology and future clinical development. [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.)
Database: Engineering Source
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Header DbId: egs
DbLabel: Engineering Source
An: 191816622
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PubType: Academic Journal
PubTypeId: academicJournal
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Items – Name: Title
  Label: Title
  Group: Ti
  Data: Rational design of selective bispecific EPO-R/CD131 agonists.
– Name: Author
  Label: Authors
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  Data: <searchLink fieldCode="AR" term="%22Doiron%2C+Kailyn+E%22">Doiron, Kailyn E</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Way%2C+Jeffrey+C%22">Way, Jeffrey C</searchLink><relatesTo>2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Silver%2C+Pamela+A%22">Silver, Pamela A</searchLink><relatesTo>2</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, p1-15. 15p.
– Name: Subject
  Label: Subjects
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  Data: <searchLink fieldCode="DE" term="%22Erythropoietin+receptors%22">Erythropoietin receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Bispecific+antibodies%22">Bispecific antibodies</searchLink><br /><searchLink fieldCode="DE" term="%22Erythropoietin%22">Erythropoietin</searchLink><br /><searchLink fieldCode="DE" term="%22Progenitor+cells%22">Progenitor cells</searchLink><br /><searchLink fieldCode="DE" term="%22Structural+models%22">Structural models</searchLink><br /><searchLink fieldCode="DE" term="%22STAT+proteins%22">STAT proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Cytokine+receptors%22">Cytokine receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+engineering%22">Protein engineering</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Erythropoietin (EPO) suppresses apoptosis and promotes survival by signaling through EPO-R/EPO-R on hematopoietic progenitors or EPO-R/CD131 on non-hematopoietic cells. However, EPO signaling through EPO-R/CD131 is controversial and there is no solved structure of a complex. Here, we constructed a structural model of EPO-R/CD131 and designed several anti-EPO-R, anti-CD131 bispecific proteins that selectively activate EPO-R/CD131. Treatment with these fusion proteins is sufficient to activate STAT5 phosphorylation downstream of EPO-R/CD131 without engaging EPO-R/EPO-R. We demonstrated that proteins with a tandem scFv or bispecific antibody format activate EPO-R/CD131, in contrast to an equimolar mixture of the individual scFvs. Finally, we explored the effect of modifications to binding domain arrangement and linker length and found results consistent with our structural model of an EPO-R/CD131 complex. These findings highlight the utility of bispecific scaffolds in the development of cytokine receptor agonists and provide a foundation for the study of EPO-R/CD131 biology and future clinical development. [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:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1093/protein/gzaf013
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 15
        StartPage: 1
    Subjects:
      – SubjectFull: Erythropoietin receptors
        Type: general
      – SubjectFull: Bispecific antibodies
        Type: general
      – SubjectFull: Erythropoietin
        Type: general
      – SubjectFull: Progenitor cells
        Type: general
      – SubjectFull: Structural models
        Type: general
      – SubjectFull: STAT proteins
        Type: general
      – SubjectFull: Cytokine receptors
        Type: general
      – SubjectFull: Protein engineering
        Type: general
    Titles:
      – TitleFull: Rational design of selective bispecific EPO-R/CD131 agonists.
        Type: main
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      – PersonEntity:
          Name:
            NameFull: Doiron, Kailyn E
      – PersonEntity:
          Name:
            NameFull: Way, Jeffrey C
      – PersonEntity:
          Name:
            NameFull: Silver, Pamela A
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          Dates:
            – D: 01
              M: 01
              Text: 2025
              Type: published
              Y: 2025
          Identifiers:
            – Type: issn-print
              Value: 17410126
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            – Type: volume
              Value: 38
          Titles:
            – TitleFull: PEDS: Protein Engineering, Design & Selection
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