Article Text

Download PDFPDF

1097 MDK1654: a branched synthetic peptide that activates both the IL-7 receptor and the βγc form of the IL-2/15 receptor
  1. Inkyung Angie Park,
  2. Steven Cwirla,
  3. Alice Bakker,
  4. Ronald Barrett,
  5. Michael Needels,
  6. Praechompoo Pongtornpipat,
  7. Blake Williams,
  8. Prarthana Joshi and
  9. William Dower
  1. Medikine, Menlo Park, CA, USA


Background Derivatives of IL-2, IL-15, and IL-7 are in clinical development as immuno-oncology agents. IL-2 and IL-15 stimulate proliferation and enhance the function of effector T cells and natural killer cells, whereas IL-7 acts on naïve and memory T cells and is crucial for persistent effector T cell generation. Combining these complementary effects on immune cells may offer benefits over either mechanism alone. We have previously described small synthetic peptidyl agonists (PEPTIKINES), unrelated to IL-2, IL-15, or IL-7, that selectively activate either IL-2/15Rβγc or IL-7Rαγc.

Methods Here we report the creation and pharmacology of a synthetic branched peptide, MDK1654, comprised of three peptide ligands binding to IL-7Rα, IL-2/15Rβ, and γc separately and linkers that are engineered to provide appropriate spatial orientation of the ligands. The in vitro pharmacology of MDK1654 was compared to non-alpha IL-2/15 or IL-7 mono-specific PEPTIKINES by signaling and immune cell proliferation.

Results MDK1654 can activate both IL-2/15Rβγc and IL-7Rαγc signaling pathways as measured by phosphorylation of STAT5 and showed full agonist activity for both receptors with EC50s <10 nM in naturally γc-expressing TF-1 cells engineered to overexpress either IL-2Rβ or IL-7Rα.

In ex vivo studies with PBMCs from 5 healthy donors, MDK1654 exhibited additive and complementary effects of IL-2/15Rβγc and IL-7Rαγc signaling among various lymphocyte subpopulations. The mono-specific non-alpha IL-2/15 and IL-7 PEPTIKINEs produced signaling patterns in lymphocyte subsets similar to those induced by IL-2v (a “non-alpha” mutant of IL-2) and IL-7, respectively. In the resting PBMCs, MDK1654 induced pSTAT5 and cell proliferation response profiles in CD8, CD4, and naïve and memory subpopulations similar to the IL-7 PEPTIKINE, including expansion of Tscm cells. In PBMCs activated with anti-CD3 antibody, a treatment known to increase IL-2/15Rβ expression, MDK1654 behaved similarly to the non-alpha IL-2/15 PEPTIKINE in most cell populations except for the Tscm population. NK cells were expanded by MDK1654 and the non-alpha IL-2/15 PEPTIKINE but not by the IL-7 PEPTIKINE.

Conclusions These data indicate that MDK1654 mimics the effect of the non-alpha binding form of IL-2/15 or IL-7, depending on the cell type. To our knowledge, this is the first demonstration of a synthetic peptide with agonist activity for two different cytokine receptors and offers an exciting new modality for cancer immunotherapy.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.