Benjamin Chalopin

Despite constant progress over the past three decades, multiple myeloma (MM) is still an incurable disease, and the identification of new biomarkers to better select patients and adapt therapy is more relevant than ever. Recently, the introduction of therapeutic monoclonal antibodies (mAbs) (including direct-targeting mAbs and immune checkpoint inhibitors) appears to have changed the paradigm of MM management, emphasizing the opportunity to cure MM patients through an immunotherapeutic approach. In this context, immuno-positron emission tomography (immunoPET), combining the high sensitivity and resolution of a PET camera with the specificity of a radiolabelled mAb, holds the capability to cement this new treatment paradigm for MM patients. It has the potential to non-invasively monitor the distribution of therapeutic antibodies or directly monitor biomarkers on MM cells, and to allow direct observation of potential changes over time and in response to various therapeutic interventions. Tumor response could, in the future, be anticipated more effectively to provide individualized treatment plans tailored to patients according to their unique imaging signatures. This work explores the important role played by immunotherapeutics in the management of MM, and focuses on some of the challenges for this drug class and the significant interest of companion imaging agents such as immunoPET.

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.