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Effectiveness of [67Cu]Cu-trastuzumab as a theranostic against HER2-positive breast cancer

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Abstract

Purpose

To evaluate the imaging and therapeutic properties (theranostic) of 67Cu-labeled anti-human epidermal growth factor receptor II (HER2) monoclonal antibody trastuzumab against HER2-positive breast cancer (BC).

Methods

We conjugated trastuzumab with p-SCN-Bn-NOTA, 3p-C-NETA-NCS, or p-SCN-Bn-DOTA, and radiolabeled with [67Cu]CuCl2. Immunoconjugate internalization was evaluated in BT-474, JIMT-1 and MCF-7 BC cells. In vitro stability was studied in human serum (HS) and Phosphate Buffered Saline (PBS). Flow cytometry, radioligand binding and immunoreactive fraction assays were carried out. ImmunoSPECT imaging of [67Cu]Cu-NOTA-trastuzumab was done in mice bearing BT-474, JIMT-1 and MCF-7 xenografts. Pharmacokinetic was studied in healthy Balb/c mice while dosimetry was done in both healthy Balb/c and in athymic nude mice bearing JIMT-1 xenograft. The therapeutic effectiveness of [67Cu]Cu-NOTA-trastuzumab was evaluated in mice bearing BT-474 and JIMT-1 xenografts after a single intravenous (i.v.) injection of ~ 16.8 MBq.

Results

Pure immunoconjugates and radioimmunoconjugates (> 95%) were obtained. Internalization was HER2 density-dependent with highest internalization observed with NOTA-trastuzumab. After 5 days, in vitro stabilities were 97 ± 1.7%, 31 ± 6.2%, and 28 ± 4% in HS, and 79 ± 3.5%, 94 ± 1.2%, and 86 ± 2.3% in PBS for [67Cu]Cu-NOTA-trastuzumab, [67Cu]Cu-3p-C-NETA-trastuzumab and [67Cu]Cu-DOTA-trastuzumab, respectively. [67Cu]Cu-NOTA-trastuzumab was chosen for further evaluation. BT-474 flow cytometry showed low KD, 8.2 ± 0.2 nM for trastuzumab vs 26.5 ± 1.6 nM for NOTA-trastuzumab. There were 2.9 NOTA molecules per trastuzumab molecule. Radioligand binding assay showed a low KD of 2.1 ± 0.4 nM and immunoreactive fraction of 69.3 ± 0.9. Highest uptake of [67Cu]Cu-NOTA-trastuzumab was observed in JIMT-1 (33.9 ± 5.5% IA/g) and BT-474 (33.1 ± 10.6% IA/g) xenograft at 120 h post injection (p.i.). Effectiveness of the radioimmunoconjugate was also expressed as percent tumor growth inhibition (%TGI). [67Cu]Cu-NOTA-trastuzumab was more effective than trastuzumab against BT-474 xenografts (78% vs 54% TGI after 28 days), and JIMT-1 xenografts (90% vs 23% TGI after 19 days). Mean survival of [67Cu]Cu-NOTA-trastuzumab, trastuzumab and saline treated groups were > 90, 77 and 72 days for BT-474 xenografts, while that of JIMT-1 were 78, 24, and 20 days, respectively.

Conclusion

[67Cu]Cu-NOTA-trastuzumab is a promising theranostic agent against HER2-positive BC.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was funded by Canadian Institute for Health Research (CIHR) Project Grants (Grant numbers 437660 and 408132) to Humphrey Fonge.

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Authors and Affiliations

  1. Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 0W8, Canada

    Jessica Pougoue Ketchemen, Fabrice Ngoh Njotu, Hanan Babeker, Anjong Florence Tikum, Emmanuel Nwangele, Nikita Henning & Humphrey Fonge

  2. Department of Pathology and Lab. Medicine, College of Medicine, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK, S7N 5A2, Canada

    Fabrice Ngoh Njotu, Hanan Babeker & Emmanuel Nwangele

  3. NURA Research Group, Belgian Nuclear Research Center (SCK CEN), Mol, Belgium

    Stephen Ahenkorah

  4. Radiopharmaceutical Research, Department of Pharmacy and Pharmacology, University of Leuven, Leuven, Belgium

    Stephen Ahenkorah & Frederik Cleeren

  5. Department of Medical Imaging, Royal University Hospital Saskatoon, Saskatoon, SK, S7N 0W8, Canada

    Humphrey Fonge

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  1. Jessica Pougoue Ketchemen
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Contributions

Experimental design, execution, and data analysis were performed by Jessica Pougoue Ketchemen, Fabrice Ngoh Njotu, Hanan Babeker, Stephen Ahenkorah, Anjong Florence Tikum, Emmanuel Nwangele, Nikita Henning, Frederik Cleeren, and Humphrey Fonge. Writing of the original draft preparation, and review were done by Jessica Pougoue Ketchemen and Humphrey Fonge. All the authors contributed to the article and approved the submitted version.

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Correspondence to Humphrey Fonge.

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Pougoue Ketchemen, J., Njotu, F.N., Babeker, H. et al. Effectiveness of [67Cu]Cu-trastuzumab as a theranostic against HER2-positive breast cancer. Eur J Nucl Med Mol Imaging 51, 2070–2084 (2024). https://doi.org/10.1007/s00259-024-06648-3

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