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Updated: Feb 4, 2026

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Next-generation anti-DLL3 radiopharmaceuticals targeting high-grade neuroendocrine lung and prostate cancers

Salomon Tendler1,2, Roberto De Gregorio2, Paul Balderes3

  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.

Proceedings of the National Academy of Sciences of the United States of America
|February 2, 2026
PubMed

Insights

Researchers developed novel anti-DLL3 radioimmunoconjugates for diagnosing and treating neuroendocrine tumors. A diagnostic tracer showed excellent tumor targeting, while a therapeutic agent significantly improved survival in small-cell lung cancer models.

Area of Science:

  • Oncology
  • Radiochemistry
  • Immunotherapy

Background:

  • Delta-like ligand 3 (DLL3) is a protein found on high-grade neuroendocrine tumors like small-cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC).
  • Targeting DLL3 offers a promising strategy for both diagnosing and treating these cancers.

Purpose of the Study:

  • To develop and evaluate novel anti-DLL3 radioimmunoconjugates for diagnostic imaging and targeted radionuclide therapy.
  • To identify lead candidates for both diagnostic and therapeutic applications against DLL3-expressing tumors.

Main Methods:

  • Generated human monoclonal antibodies (mAbs) against DLL3 using transgenic mice.
  • Screened mAbs for high affinity and internalizing properties against diverse DLL3 epitopes.
  • Developed diagnostic (89Zr-labeled) and therapeutic (177Lu-labeled) radioimmunoconjugates.
  • Evaluated candidates using in vivo immunoPET imaging and therapeutic efficacy studies in SCLC and NEPC mouse models.

Main Results:

  • Identified [89Zr]Zr-DFO-TDI-Y-010 as a lead diagnostic tracer with excellent tumor-to-background ratios (>4) in SCLC models.
  • [177Lu]Lu-CHX-A"-DTPA-TDI-Y-010 demonstrated significant antitumor effects and improved overall survival in SCLC models.
  • The therapeutic agent showed comparable overall survival in a NEPC model.

Conclusions:

  • Developed effective anti-DLL3 radioimmunoconjugates for both diagnosis and therapy of neuroendocrine tumors.
  • The lead diagnostic tracer and therapeutic agent show significant potential for clinical translation.
  • DLL3-targeted radioimmunotherapy offers a promising approach for SCLC and NEPC treatment.
Keywords:
DLL3Lutetium-177NEPCSCLCTheranostics

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