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Imaging xCT with Immuno-PET in Therapy-Resistant Non-Small Cell Lung Cancer.

Abigail R Barber1, Richard S Edwards1, Sofia N Dos Santos1

  • 1School of Biomedical Engineering and Imaging Sciences, King's College London, St. Thomas' Hospital, London, United Kingdom.

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
|June 18, 2026
PubMed
Summary

Researchers developed an immuno-PET radiotracer to noninvasively assess amino acid transporter xCT in non-small cell lung cancer (NSCLC). This tool images xCT expression and antibody delivery, aiding development of new therapies for treatment-resistant NSCLC.

Keywords:
immuno-PETmolecular imagingnon–small cell lung cancertherapy resistancexCT

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Area of Science:

  • Nuclear Medicine
  • Oncology
  • Molecular Imaging

Background:

  • Therapy resistance is a major challenge in non-small cell lung cancer (NSCLC), linked to high mortality rates.
  • Overexpression of the amino acid transporter xCT is a frequent mechanism of treatment resistance in NSCLC.
  • Targeting xCT with antibody-drug conjugates offers a potential therapeutic strategy.

Purpose of the Study:

  • To develop an immuno-PET radiotracer for noninvasive evaluation of xCT expression in NSCLC.
  • To visualize the pharmacokinetics of xCT-targeting antibodies in vivo.
  • To assess the potential of immuno-PET in guiding the development of antibody-based therapies for resistant NSCLC.

Main Methods:

  • Specificity of xCT-targeting antibodies (HM30, HM34) confirmed via Western blot, immunocytochemistry, and internalization studies.
  • Antibodies conjugated to deferoxamine and radiolabeled with 89Zr; immunoreactivity assessed.
  • Preclinical in vivo pharmacokinetics evaluated using longitudinal immuno-PET imaging and ex vivo biodistribution in NSCLC models.

Main Results:

  • Developed 89Zr-labeled immuno-PET agents ([89Zr]Zr-DFO-HM30, [89Zr]Zr-DFO-HM34) with good yield and purity, retaining immunoreactivity.
  • Agents successfully delineated high xCT-expressing tumors in vivo, with low binding in tumors expressing low xCT.
  • Imaging and autoradiography confirmed lesion-specific binding of [89Zr]Zr-DFO-HM30 in orthotopic lung tumors.

Conclusions:

  • Immuno-PET is a viable research tool for imaging elevated xCT expression in NSCLC.
  • The developed radiotracers can visualize tumor penetration of xCT-directed antibodies.
  • This imaging approach can inform the development of improved antibody therapies for treatment-resistant NSCLC, potentially improving patient survival.