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A research team at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) has developed a radiopharmaceutical molecule marker that can visualize tumors that carry the cell surface protein Nectin-4. This primarily occurs in the body in cases of urothelial carcinoma, a common form of bladder cancer. In pre-clinical trials, the drug candidate, NECT-224, proved stable and was successfully used in humans for the first time. As the team has now reported in the Journal of Medicinal Chemistry (DOI: https://doi.org/10.1021/acs.jmedchem.5c02371), in the future, it could be used to better identify patients who would benefit from Nectin-4 -targeted therapies.
A research team at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) has developed a radiopharmaceutical molecule marker that can visualize tumors that carry the cell surface protein Nectin-4. This primarily occurs in the body in cases of urothelial carcinoma, a common form of bladder cancer. In pre-clinical trials, the drug candidate, NECT-224, proved stable and was successfully used in humans for the first time. As the team has now reported in the Journal of Medicinal Chemistry (DOI: https://doi.org/10.1021/acs.jmedchem.5c02371), in the future, it could be used to better identify patients who would benefit from Nectin-4 -targeted therapies.
Many modern cancer drugs only work when the target structure to which they are supposed to bind is also present on the tumor cells. In the case of urothelial carcinoma, the cell surface protein Nectin-4 lends itself to this purpose. It serves as a “door sign” for antibody-coupled agents that are able to eliminate tumor cells in a targeted fashion. But not every tumor produces the same amount of Nectin-4. Metastases, that is, secondary tumors that spread from the primary tumor, can even lose the protein, resulting in the therapies being less effective. Up to now, there has been no non-invasive method for reliably determining the content and heterogeneity of Nectin-4 by imaging prior to therapy – an obstacle to making precise treatment decisions.
In order to solve this problem, HZDR researchers chemically modified the bicyclic peptide drug conjugate BT8009 to make it suitable for diagnostic imaging. Their approach is based on radiotracers: molecules labeled with a radionuclide which bind specifically to certain structures in the body and whose distribution can be determined with the help of imaging techniques like positron emission tomography (PET). This allows researchers to trace whether and where the active agent in the body binds to its target structure non-invasively.
The researchers chose a so-called bicyclic peptide as their carrier molecule. This class of molecules is characterized by high targeting accuracy and good stability in the body. By chemical modification – including replacing an oxidation-sensitive amino acid – a series of robust peptide variants was produced that can be labeled with radioactive isotopes like Gallium-68 and Copper-64. Nectin-4 can be revealed in both variants using PET, but they differ in their diagnostic application: Gallium-68 enables fast, same-day nuclear medical PET examinations while, due to its longer half-life, Copper-64 allows potentially higher-contrast images to be achieved at a later date.
First application at Dresden University Hospital
The new tracers initially underwent in-depth testing in cell cultures and, subsequently, in pre-clinical tumor models. Labeled with Gallium-68 or Copper-64, NECT-224, in particular, revealed high binding specificity, clear tumor localization, and rapid clearance from the surrounding tissue – important preconditions for precise PET imaging. These convincing results paved the way for the first clinical application. In summer 2025 at Carl Gustav Carus University Hospital Dresden, the Gallium-68 variant of NECT-224 was used on a patient for the first time. The PET images clearly presented the tumor and thus confirmed the pre-clinical results on the suitability of NECT-224.
“Using NECT-224 we can reveal whether a tumor really does carry Nectin-4 so that we can judge whether the patient affected will respond to targeted therapies,” explains Dr. Robert Wodtke, research associate at HZDR’s Institute of Radiopharmaceutical Cancer Research. “For us, the first successful use in humans was an important milestone and a strong signal that this tracer can offer genuine clinical added value.”
Further development and theranostic potential
Alongside clinical trials, the research team is working on further optimizing NECT-224. Their aim is to extend the residence time in the tumor tissue and to test the tracer’s suitability for future theranostic approaches – that is, concepts that interlink diagnosis and therapy even more closely. In the long term, this would not only mean the marker could help to select appropriate therapies but also serve as a basis for new treatment strategies, known as “targeted radioligand therapies” (TRTs).
The development of NECT-224 was facilitated by the EU research project, UroNec, which is supported by the Development Bank of Saxony. In addition to the trials at Dresden University Hospital, development of the radiotracer is being driven by close cooperation with partners in industry: ROTOP Pharmaka GmbH in Dresden-Rossendorf and CUP Laboratories Dr. Freitag GmbH in Radeberg. The project is thus a successful example of research transfer between science, industry and clinical practice in Saxony. Moreover, it demonstrates the strength of nukliD, the growing Radiopharmacy Cluster Dresden, in which several actors in the field have amalgamated. The network aims to establish the region as one of the leading radiopharmacy centers.
Dr. Robert Wodtke
Institute of Radiopharmaceutical Cancer Research at HZDR
Research Associate
Phone: +49 351 260 4033 | Email: r.wodtke[at]hzdr.de
Prof. Klaus Kopka
Institute of Radiopharmaceutical Cancer Research at HZDR
Institute Director
Phone: +49 351 260 2060 | Email: k.kopka[at]hzdr.de
T. Krönke, J. Trommer, M. Ullrich, M. Laube, R. Löser, J. Kretzschmar, M. Urbanova, S. Stadlbauer, F. Brandt, I. Platzek. S. Hoberück, J. Kotzerke, C. Thomas, M. Miederer, A. Bundschuh, K. Kopka, J. Pietzsch, R. Wodtke: ”Precision on Two Wheels” – Structural Refinement of 64Cu- and 68Ga-Labeled Bicyclic Peptides Targeting Nectin-4 for Improved Tumor Imaging: From Preclinical Development to First-in-Human Application, in Journal of Medicinal Chemistry, 2025 (DOI: https://doi.org/10.1021/acs.jmedchem.5c02371).
This artistic representation illustrates how NECT-224 works: bicyclic peptides labeled with radioact ...
Quelle: HZDR/A.Gruetzner
In the laboratory, Johanna Trommer and Tobias Krönke use a microwave-assisted peptide synthesizer to ...
Quelle: HZDR/K.Zheynova
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