Investigational New Drugs

, Volume 37, Issue 1, pp 9–16 | Cite as

Inhibiting IL-2 signaling and the regulatory T-cell pathway using computationally designed peptides

  • Tammy Price-Troska
  • Zhi-Zhang YangEmail author
  • David Diller
  • Alexander Bayden
  • Mark Jarosinski
  • Joseph Audie
  • Stephen M. AnsellEmail author


Background Increased serum levels of soluble interleukin-2 (IL-2) receptor alpha (sIL-2Rα) are an indicator of poor prognosis in patients with B-cell non-Hodgkin lymphoma (NHL). By binding to IL-2, sIL-2Rα upregulates Foxp3 expression and induces the development of regulatory T (Treg) cells. Methods To inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of Foxp3 and decreasing Treg cell numbers, we developed peptides by structure-based computational design to disrupt the interaction between IL-2 and sIL-2Rα. Each peptide was screened using an enzyme-linked immunosorbent assay (ELISA), and 10 of 22 peptides showed variable capacity to inhibit IL-2/sIL-2Rα binding. Results We identified a lead candidate peptide, CMD178, which consistently reduced the expression of Foxp3 and STAT5 induced by IL-2/sIL-2Rα signaling. Furthermore, production of cytokines (IL-2/interferon gamma [IFN-γ]) and granules (perforin/granzyme B) was preserved in CD8+ T cells co-cultured with IL-2–stimulated CD4+ T cells that had been pretreated with CMD178 compared to CD8+ cells co-cultured with untreated IL-2–stimulated CD4+ T cells where it was inhibited. Conclusions We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/sIL-2Rα signaling and inhibit Treg cell development. We anticipate that these peptides will have therapeutic potential in B-cell NHL and other malignancies.


Computationally designed peptides Foxp3 Soluble IL-2Ra STAT5 Treg cells 



This work was supported in part by grants from the National Institutes of Health (P50 CA97274), the Leukemia & Lymphoma Society, the Landow Foundation, and the Predolin Foundation.

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

Ethical approval

The authors declared that this article does not contain any studies with human or animal participants.

Informed consent

For this type of study, formal consent is not required.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Tammy Price-Troska
    • 1
  • Zhi-Zhang Yang
    • 1
    Email author
  • David Diller
    • 2
    • 3
  • Alexander Bayden
    • 2
    • 4
  • Mark Jarosinski
    • 2
  • Joseph Audie
    • 2
    • 5
  • Stephen M. Ansell
    • 1
    Email author
  1. 1.Division of Hematology, Department of MedicineMayo ClinicRochesterUSA
  2. 2.CMD Bioscience, Inc.New HavenUSA
  3. 3.Data2 Discovery ConsultingEast WindsorUSA
  4. 4.IDEAYA Biosciences, Inc.CaliforniaUSA
  5. 5.Sacred Heart UniversityFairfieldUSA

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