1. Preclinical Evaluation of Mesothelin-Specific Ligands for SPECT Imaging of Triple-Negative Breast Cancer
- Author
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Brigitte Kerfelec, Mitra Ahmadi, Audrey Soubies, Marlène Debiossat, Daniel Fagret, Pascale Perret, Daniel Baty, Alexis Broisat, Catherine Ghezzi, Christopher Montemagno, Sandrine Bacot, Laurent Riou, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Radiopharmaceutiques biocliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Université Joseph Fourier - Grenoble 1 (UJF), This work was partly funded by grant ANR-11-INBS-0006 from France Life Imaging., ANR-11-INBS-0006,FLI,France Life Imaging(2011), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Kerfelec, Brigitte, Perret, Pascale, Infrastructures - France Life Imaging - - FLI2011 - ANR-11-INBS-0006 - INBS - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)
- Subjects
0301 basic medicine ,[SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging ,Triple Negative Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine ,GPI-Linked Proteins ,Ligands ,[SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Breast cancer ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,In vivo ,Trastuzumab ,Spect imaging ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Mesothelin ,Tissue Distribution ,Triple-negative breast cancer ,ComputingMilieux_MISCELLANEOUS ,Tomography, Emission-Computed, Single-Photon ,nuclear imaging ,biology ,business.industry ,Cancer ,Organotechnetium Compounds ,mesothelin ,medicine.disease ,3. Good health ,030104 developmental biology ,Cell Transformation, Neoplastic ,[SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging ,030220 oncology & carcinogenesis ,Isotope Labeling ,SPECT ,Cancer research ,biology.protein ,Female ,business ,Hydrophobic and Hydrophilic Interactions ,TNBC ,Ex vivo ,medicine.drug - Abstract
International audience; Mesothelin is a cell-surface glycoprotein restricted to mesothelial cells overexpressed in several types of cancer, including triple-negative breast cancer not responding to trastuzumab or hormone-based therapies. Mesothelin-targeting therapies are currently being developed. However, the identification of patients potentially eligible for such a therapeutic strategy remains challenging. The objective of this study was to perform the radiolabeling and preclinical evaluation of 99mTc-A1 and 99mTc-C6, two antimesothelin single-domain antibody (sdAb)-derived imaging agents. Methods: A1 and C6 were radiolabeled with 99mTc and evaluated in vitro on recombinant protein and cells, as well as in vivo in xenograft mouse models of the triple-negative breast cancer cell lines HCC70 (mesothelin-positive) and MDA-MB-231 (mesothelin-negative). Results: Both 99mTc-A1 and 99mTc-C6 bound mesothelin with high affinity in vitro, with 99mTc-A1 affinity being 2.4-fold higher than that of 99mTc-C6 (dissociation constant, 43.9 ± 4.0 vs. 107 ± 16 nM, P < 0.05). 99mTc-A1 and 99mTc-C6 remained stable in vivo in murine blood (>80% at 2 h) and ex vivo in human blood (>90% at 6 h). In vivo 99mTc-A1 uptake (percentage injected dose) in HCC70 tumors was 5-fold higher than in MDA-MB-231 tumors and 1.5-fold higher than that of 99mTc-C6 (2.34% ± 0.36% vs. 0.48% ± 0.18% and 1.56% ± 0.43%, respectively, P < 0.01) and resulted in elevated tumor-to-background ratios. In vivo competition experiments demonstrated the specificity of 99mTc-A1 uptake in HCC70 tumors. Conclusion: Mesothelin-positive tumors were successfully identified by SPECT using 99mTc-A1 and 99mTc-C6. Considering its superior characteristics, 99mTc-A1 was selected as the most suitable tool for further clinical translation.
- Published
- 2018