PET Imaging of Multiple Myeloma : Comparison of 89Zr- and 64Cu-labeled anti-CD138 Conjugates to 64CuCl2 and 18F-FDG in a Preclinical Syngeneic Model

Abstract : Purpose: Although recent data from the literature suggest that PET imaging with [18]-Fluorodeoxyglucose (18F-FDG) is a promising technique in multiple myeloma (MM), the development of other radiopharmaceuticals seems relevant. CD138 is currently used as a standard marker in many laboratories for the identification and purification of myeloma cells, and could be used in phenotype tumor imaging. In this study, we evaluated 2 conjugates of an anti-CD138 murine antibody (9E7.4) and compared them to metabolic tracers (64CuCl2and 18F-FDG) for PET imaging in a MM syngeneic mouse model. Subjects and Methods: 9E7.4 was conjugated to TE2A-benzyl isothiocyanate (TE2A) and desferrioxamine (DFO) chelators for copper-64 (64Cu) and zirconium- 89 (89Zr) labeling. 64Cu-TE2A-9E7.4 and 89Zr-DFO-9E7.4 antibodies and 64CuCl2 were evaluated via PET imaging and biodistribution studies in C57BL / KaLwRij mice bearing either 5T33-MM subcutaneous tumors or bone lesions. These results were compared to 18F-FDG-PET imaging. Autoradiography and histology of representative tumors were secondly conducted. Results: In biodistribution and PET studies, 64Cu-TE2A-9E7.4 and89Zr-DFO-9E7.4displayed comparable good tumor uptake of subcutaneous tumors. On the opposite, only low-level concentrations of 64CuCl2 were accumulated in MM lesions. PET/CT imaging of the disseminated model with 64Cu TE2A-9E7.4 and 89Zr-DFO-9E7.4 showed high uptake of the probes at the site of intra-medullary lesions, greater than that demonstrated with 18F-FDG-PET and correlating with the bioluminescence imaging of the tumor. Histopathologic analysis of the immuno-PET-positive lesions also confirmed the presence of plasma cell infiltrates within the bone marrow. Comparison of both 9E7.4 conjugates revealed higher non specific bone uptakes of 89Zr-DFO-9E7.4 than 64Cu-TE2A-9E7.4 (3.1±1.15 vs 1.48±0.29 respectively at 24h PI; p=0.0061; non-parametric test) while the opposite was observed for tumor-to-blood ratio (1.42±0.24 vs 4.08±1.09 respectively at 24h PI; p=0.0391; non-parametric test). Such observations were consistent with the known in vivo gradual transchelation of 89Zr over time which could reduce the efficacy of a 89Zr-labeled immuno-PET probe as an effective tool for bone lesions imaging. Conclusion: 64Cu- and 89Zr-labeled anti-CD138 antibody can detect subcutaneous MM tumors and bone marrow lesions with high sensitivity, outperforming 18F-FDG-PET and 64CuCl2 in this preclinical model. 64Cu- anti-CD138 antibody had the most optimal tumor-to-nontarget tissue ratios for translation into humans as a specific and promising new imaging radiopharmaceutical agent in MM.
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https://www.hal.inserm.fr/inserm-02341452
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Submitted on : Thursday, October 31, 2019 - 1:39:29 PM
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Clément Bailly, Sébastien Gouard, Benjamin Chalopin, Thomas Carlier, Catherine Sai-Maurel, et al.. PET Imaging of Multiple Myeloma : Comparison of 89Zr- and 64Cu-labeled anti-CD138 Conjugates to 64CuCl2 and 18F-FDG in a Preclinical Syngeneic Model. European Journal of Nuclear Medicine and Molecular Imaging, Springer Verlag (Germany), 2018, 45 (1), pp.S20-S21. ⟨inserm-02341452⟩

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