Efficacy of a HER2-Targeted Thorium-227 Conjugate in a HER2-Positive Breast Cancer Bone Metastasis Model
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Compounds
2.2. Cell Culture
2.3. Synthesis and Characterization of HER2-TTC
2.4. In Vitro Cytotoxicity of HER2-TTC
2.5. In Vitro Mode-of-Action of HER2-TTC
2.6. In Vivo Efficacy of HER2-TTC in Various Xenograft Models
2.7. In Vivo Mode-of-Action Analyses in the Calu-3 Model
2.8. Radiography and Micro-CT Analyses in the BT-474 Model
2.9. Alpha Camera Imaging and Gamma Counting in the BT-474 Model
2.10. Histology and Histomorphometry Analyses in the BT-474 Model
2.11. Biochemical Marker Analysis in the BT-474 Model
2.12. Detection of HER2 Expression in Patient Samples
2.13. Statistical Analyses
3. Results
3.1. HER2-TTC Shows Specific and Potent Binding in Various HER2-Expressing Cancer Cells
3.2. HER2-TTC Reduces Cell Viability and Induces DNA Double Strand Break Formation and Cell Cycle Arrest In Vitro
3.3. HER2-TTC Shows Dose-Dependent Antitumor Efficacy in Subcutaneous KPL-4 and Calu-3 Xenograft Models
3.4. HER2-TTC Inhibits Intratibial Tumor Growth and Tumor-Induced Abnormal Bone Formation in a BT-474 Mouse Model Mimicking Breast Cancer Metastasized to Bone
3.5. HER2-TTC Accumulates in Bone at Sites of Active Bone Turnover
3.6. HER2 Is Expressed in Samples from the BT-474 Mouse Model Mimicking Bone Metastases
3.7. HER2 Expression Is Detected in Bone Metastasis Samples from HER2-Positive Breast Cancer Patients
4. Discussion
5. Conclusions
6. Patents
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cell Line | HER2 Expression Level (ABC) | In Vitro Binding EC50 (nM, Mean ± SD) | In Vitro Cytotoxicity | ||
---|---|---|---|---|---|
HER2 mAb | HER2- ACC | Specific Activity (kBq/µg) | IC50, HER2-TTC (kBq/mL, Mean ± SD) | ||
BT-474 | 550,000 | 2.7 | 2.1 | 40 | 1.8 ± 1.2 |
20 | 0.8 | ||||
SK-BR-3 | 500,000 | 2.4 | 2.4 | 40 | 0.2 ± 0.1 |
10 | 0.1 | ||||
Calu-3 | 420,000 | 3.9 ± 0.6 | 5.0 ± 0.4 | 40 | 0.03 ± 0.02 |
10 | 0.02 | ||||
KPL-4 | 280,000 | 2.0 ± 0.7 | 2.5 ± 0.4 | 40 | 0.2 ± 0.1 |
20 | 0.2 ± 0.1 | ||||
10 | 0.3 ± 0.1 |
Patient Number | Sample Type | HER2 Score (1–3) | Focal (F)/Homogeneous (H) Expression |
---|---|---|---|
1 | Breast cancer | 2 | F |
Bone metastasis | 3 | F | |
2 | Breast cancer | 1 | F |
Bone metastasis | 1 | H | |
3 | Breast cancer | 2 | H |
Bone metastasis | 2 | F | |
4 | Breast cancer | 1 | H |
Bone metastasis | 1 | F | |
5 | Breast cancer | 3 | H |
Bone metastasis | 3 | F | |
6 | Breast cancer | 3 | F |
Bone metastasis | 0 | H | |
7 | Breast cancer | 3 | H |
Bone metastasis | 2 | F | |
8 | Breast cancer | n.a. | n.a. |
Bone metastasis | 1 | F |
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Karlsson, J.; Hagemann, U.B.; Cruciani, V.; Schatz, C.A.; Grant, D.; Ellingsen, C.; Kristian, A.; Katoozi, S.; Mihaylova, D.; Uran, S.R.; et al. Efficacy of a HER2-Targeted Thorium-227 Conjugate in a HER2-Positive Breast Cancer Bone Metastasis Model. Cancers 2023, 15, 3419. https://doi.org/10.3390/cancers15133419
Karlsson J, Hagemann UB, Cruciani V, Schatz CA, Grant D, Ellingsen C, Kristian A, Katoozi S, Mihaylova D, Uran SR, et al. Efficacy of a HER2-Targeted Thorium-227 Conjugate in a HER2-Positive Breast Cancer Bone Metastasis Model. Cancers. 2023; 15(13):3419. https://doi.org/10.3390/cancers15133419
Chicago/Turabian StyleKarlsson, Jenny, Urs B. Hagemann, Véronique Cruciani, Christoph A. Schatz, Derek Grant, Christine Ellingsen, Alexander Kristian, Shirin Katoozi, Dessislava Mihaylova, Steinar R. Uran, and et al. 2023. "Efficacy of a HER2-Targeted Thorium-227 Conjugate in a HER2-Positive Breast Cancer Bone Metastasis Model" Cancers 15, no. 13: 3419. https://doi.org/10.3390/cancers15133419