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Effectiveness of [ 67 Cu]Cu-trastuzumab as a theranostic against HER2-positive breast cancer.
- Source :
-
European journal of nuclear medicine and molecular imaging [Eur J Nucl Med Mol Imaging] 2024 Jun; Vol. 51 (7), pp. 2070-2084. Date of Electronic Publication: 2024 Feb 20. - Publication Year :
- 2024
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Abstract
- Purpose: To evaluate the imaging and therapeutic properties (theranostic) of <superscript>67</superscript> Cu-labeled anti-human epidermal growth factor receptor II (HER2) monoclonal antibody trastuzumab against HER2-positive breast cancer (BC).<br />Methods: We conjugated trastuzumab with p-SCN-Bn-NOTA, 3p-C-NETA-NCS, or p-SCN-Bn-DOTA, and radiolabeled with [ <superscript>67</superscript> Cu]CuCl <subscript>2</subscript> . 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 [ <superscript>67</superscript> Cu]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 [ <superscript>67</superscript> Cu]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.<br />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 [ <superscript>67</superscript> Cu]Cu-NOTA-trastuzumab, [ <superscript>67</superscript> Cu]Cu-3p-C-NETA-trastuzumab and [ <superscript>67</superscript> Cu]Cu-DOTA-trastuzumab, respectively. [ <superscript>67</superscript> Cu]Cu-NOTA-trastuzumab was chosen for further evaluation. BT-474 flow cytometry showed low K <subscript>D</subscript> , 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 K <subscript>D</subscript> of 2.1 ± 0.4 nM and immunoreactive fraction of 69.3 ± 0.9. Highest uptake of [ <superscript>67</superscript> Cu]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). [ <superscript>67</superscript> Cu]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 [ <superscript>67</superscript> Cu]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.<br />Conclusion: [ <superscript>67</superscript> Cu]Cu-NOTA-trastuzumab is a promising theranostic agent against HER2-positive BC.<br /> (© 2024. Crown.)
- Subjects :
- Animals
Humans
Mice
Female
Cell Line, Tumor
Tissue Distribution
Theranostic Nanomedicine methods
Radiopharmaceuticals therapeutic use
Radiopharmaceuticals pharmacokinetics
Radiopharmaceuticals chemistry
Immunoconjugates therapeutic use
Immunoconjugates chemistry
Immunoconjugates pharmacology
Immunoconjugates pharmacokinetics
Breast Neoplasms diagnostic imaging
Breast Neoplasms drug therapy
Trastuzumab therapeutic use
Trastuzumab pharmacology
Trastuzumab chemistry
Trastuzumab pharmacokinetics
Receptor, ErbB-2 metabolism
Copper Radioisotopes
Subjects
Details
- Language :
- English
- ISSN :
- 1619-7089
- Volume :
- 51
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- European journal of nuclear medicine and molecular imaging
- Publication Type :
- Academic Journal
- Accession number :
- 38376808
- Full Text :
- https://doi.org/10.1007/s00259-024-06648-3