What is the Best Radionuclide for Immuno-PET of Multiple Myeloma? A Comparison Study Between 89Zr- and 64Cu-Labeled Anti-CD138 in a Preclinical Syngeneic Model.

Clément Bailly,Patricia Remaud-Le Saëc,Ferid Haddad,Sébastien Gouard,Michel Chérel,Caroline Bodet-Milin,Benjamin Chalopin,Mickaël Bourgeois,Latifa Rbah-Vidal,François Guérard,Nicolas Chouin,Françoise Kraeber-Bodéré,Alain Faivre-Chauvet,Thomas Carlier,Raphaël Tripier

doi:10.3390/ijms20102564

Abstract

Although positron emission tomography (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 for the identification of myeloma cells and could be used in phenotype tumor imaging. In this study, we used an anti-CD138 murine antibody (9E7.4) radiolabeled with copper-64 (64Cu) or zirconium-89 (89Zr) and compared them in a syngeneic mouse model to select the optimal tracers for MM PET imaging. Then, 9E7.4 was conjugated to TE2A-benzyl isothiocyanate (TE2A) and desferrioxamine (DFO) chelators for 64Cu and 89Zr labeling, respectively. 64Cu-TE2A-9E7.4 and 89Zr-DFO-9E7.4 antibodies were evaluated by PET imaging and biodistribution studies in C57BL/KaLwRij mice bearing either 5T33-MM subcutaneous tumors or bone lesions and were compared to 18F-FDG-PET imaging. In biodistribution and PET studies, 64Cu-TE2A-9E7.4 and 89Zr-DFO-9E7.4 displayed comparable good tumor uptake of subcutaneous tumors. On the bone lesions, PET imaging with 64Cu-TE2A-9E7.4 and 89Zr-DFO-9E7.4 showed higher uptake than with 18F-FDG-PET. Comparison of both 9E7.4 conjugates revealed higher nonspecific bone uptakes of 89Zr-DFO-9E7.4 than 64Cu-TE2A-9E7.4. Because of free 89Zr’s tropism for bone when using 89Zr-anti-CD138, 64Cu-anti-CD138 antibody had the most optimal tumor-to-nontarget tissue ratios for translation into humans as a specific new imaging radiopharmaceutical agent in MM.

Highlights

Over the last 30 years, major advances have been made with regard to the management of multiple myeloma (MM) [1,2]
In the past several years, our group has proven that radioimmunotherapy (RIT) combining anti-CD138 monoclonal antibodies (mAbs) and alpha-emitters radionuclides is effective in an immuno-competent preclinical MM model and is feasible in humans [14,15]
We report the preclinical evaluation of a novel positron emission tomography (PET) imaging agent based on the 89Zr-labeled anti-mouse syndecan-1 mAb (9E7.4, IgG2a κ isotype) [19] in a subcutaneous model and a bone marrow disseminated MM model using desferrioxamine B (DFO) as chelator

Summary

Introduction

Over the last 30 years, major advances have been made with regard to the management of multiple myeloma (MM) [1,2] These improvements have occurred along with our evolving understanding of this malignancy [3]. Anti-CD138 immuno-PET has the potential to improve MM imaging, especially regarding lesions with low metabolic activity [10,11]. It could be considered as a companion agent for currently developed therapies targeting CD138 [12,13]. In the past several years, our group has proven that radioimmunotherapy (RIT) combining anti-CD138 mAb and alpha-emitters radionuclides is effective in an immuno-competent preclinical MM model and is feasible in humans [14,15]

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Discussion

Conclusion