2. Academic Validation
  3. Tuning of G-CSFR signaling by de novo designed agonists

Tuning of G-CSFR signaling by de novo designed agonists

  • Mol Ther. 2025 Aug 29:S1525-0016(25)00661-6. doi: 10.1016/j.ymthe.2025.08.031.
Timo Ullrich 1,  Christoph Pollmann 2,  Malte Ritter 3,  Jérémy Haaf 3,  Narges Aghaallaei 3,  Ivan Tesakov 3,  Valeriia Hatskovska 4,  Maya El-Riz 2,  Kateryna Maksymenko 1,  Sergey Kandabarau 3,  Maksim Klimiankou 3,  Claudia Lengerke 5,  Karl Welte 6,  Birte Hernandez-Alvarez 7,  Patrick Müller 8,  Andrei Lupas 7,  Jacob Piehler 2,  Julia Skokowa 9,  Mohammad ElGamacy 10
Affiliations

Affiliations

  • 1 Max Planck Institute for Biology, Department Protein Evolution, 72076 Tübingen, Germany; Friedrich Miescher Laboratory of the Max Planck Society, 72076 Tübingen, Germany.
  • 2 Department of Biology/Chemistry and Center for Cellular Nanoanalytics, Osnabrück University, 49076 Osnabrück, Germany.
  • 3 Internal Medicine II, University Hospital Tübingen, 72076 Tübingen, Germany.
  • 4 Max Planck Institute for Biology, Department Protein Evolution, 72076 Tübingen, Germany; Internal Medicine II, University Hospital Tübingen, 72076 Tübingen, Germany.
  • 5 Internal Medicine II, University Hospital Tübingen, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) partner site Tübingen, a partnership between DKFZ and University Hospital Tübingen, Germany.
  • 6 Internal Medicine II, University Hospital Tübingen, 72076 Tübingen, Germany; University Children's Hospital Tübingen, 72076 Tübingen, Germany.
  • 7 Max Planck Institute for Biology, Department Protein Evolution, 72076 Tübingen, Germany.
  • 8 Friedrich Miescher Laboratory of the Max Planck Society, 72076 Tübingen, Germany.
  • 9 Internal Medicine II, University Hospital Tübingen, 72076 Tübingen, Germany. Electronic address: julia.skokowa@med.uni-tuebingen.de.
  • 10 Max Planck Institute for Biology, Department Protein Evolution, 72076 Tübingen, Germany; Friedrich Miescher Laboratory of the Max Planck Society, 72076 Tübingen, Germany; Internal Medicine II, University Hospital Tübingen, 72076 Tübingen, Germany. Electronic address: julia.skokowa@med.uni-tuebingen.de.
PMID: 40886048 DOI: 10.1016/j.ymthe.2025.08.031
Abstract

Enhancing cytokine-based therapies by systematically tuning how an agonist associates its receptor is emerging as a powerful new concept in drug discovery. Here, we report the design and characterization of agonists that tune the granulocyte-colony stimulating factor receptor (G-CSFR) activity, which is central for the proliferation and granulocytic differentiation of hematopoietic stem cells. Using design agonists, we study the impact of varying the receptor-binding affinity and dimerization geometry on receptor association, downstream signaling, and cellular response. Hence, we achieved agonists with altered signaling specificities that are hyper-thermostable, can outcompete the native ligand (G-CSF), and bias cells toward granulopoietic differentiation over triggering proliferation. Furthermore, the design agonists differentially modulate the kinetics and amplitudes of signal transduction pathways, and gene expression patterns. In contrast to G-CSF, they achieve more selective activation of gene sets with hematopoietic functions with minimal unwanted effects on immunomodulatory signaling. These findings demonstrate the potential of dissecting the complex G-CSFR signaling, and open up ways for new therapeutic applications for designed cytokines.

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