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

• Published in: Investigational new drugs Vol. 37; no. 1; pp. 9 - 16
• Main Authors: Price-Troska, Tammy, Yang, Zhi-Zhang, Diller, David, Bayden, Alexander, Jarosinski, Mark, Audie, Joseph, Ansell, Stephen M.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2019; Springer Nature B.V
• Subjects: Binding; CD4 antigen; CD8 antigen; Cells, Cultured; Computer applications; Computer-Aided Design; Cytokines; Enzyme-linked immunosorbent assay; Foxp3 protein; Granzyme B; Humans; Interferon; Interleukin 2; Interleukin-2 - antagonists & inhibitors; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Medicine; Medicine & Public Health; Oncology; Peptide Fragments - pharmacology; Peptide inhibitors; Peptides; Perforin; Pharmacology/Toxicology; Preclinical Studies; Receptors, Interleukin-2 - antagonists & inhibitors; Serum levels; Signaling; Stat5 protein; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; γ-Interferon; STAT5; cells; T; Foxp3; Computationally designed peptides; Soluble IL-2Ra; Treg cells
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-018-0606-9

Summary 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 (T reg ) cells. Methods To inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of Foxp3 and decreasing T reg 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 T reg cell development. We anticipate that these peptides will have therapeutic potential in B-cell NHL and other malignancies.