CD46-targeted theranostics for Positron Emission Tomography and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma.

PURPOSE: Multiple myeloma (MM) is a plasma cell malignancy with an unmet clinical need for improved imaging methods and therapeutics. Recently, we identified CD46 as an overexpressed therapeutic target in MM and developed the antibody YS5, which targets a cancer-specific epitope on this protein. Herein, we validate [89Zr]Zr-DFO-YS5 for immunoPET imaging and [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of MM in murine models.

EXPERIMENTAL DESIGN: In vitro saturation binding was performed using the CD46 expressing MM.1S MM cell line. ImmunoPET imaging using [89Zr]Zr-DFO-YS5 was performed in immunodeficient (NSG) mice bearing subcutaneous and disseminated MM xenografts. For radioligand therapy, [225Ac]Ac-DOTA-YS5 was prepared, and fractionated dose treatment studies were performed in mice bearing MM1.S-Luc disseminated xenografts. Tumor burden was analyzed using BLI, and body weight and overall survival were recorded.

RESULTS: [89Zr]Zr-DFO-YS5 demonstrated high affinity for CD46 expressing MM.1S MM cells (Kd = 16.3 nM). Bioinformatics analysis of human MM samples revealed high CD46 expression. [89Zr]Zr-DFO-YS5 PET/CT specifically detected MM lesions, with low uptake in controls. In the MM.1S disseminated model, localization of uptake on PET imaging correlated well with the luciferase expression from tumor cells. A treatment study using [225Ac]Ac-DOTA-YS5 in the MM.1S disseminated model demonstrated a clear tumor volume and survival benefit in the treated groups.

CONCLUSIONS: Our study showed that the CD46-targeted probe [89Zr]Zr-DFO-YS5 can successfully image CD46-expressing MM xenografts in murine models, and [225Ac]Ac-DOTA-YS5 can effectively inhibit the growth of MM. These results demonstrate that CD46 is a promising theranostic target for MM, with the potential for clinical translation.