161Tb Radiopharmaceutical Therapy as a Treatment for RANKL-Positive Multiple Myeloma

ABSTRACT Background Denosumab, an anti-RANKL monoclonal antibody, is clinically approved for bone protection in multiple myeloma (MM) but lacks direct cytotoxic effects on tumor cells. Herein, we repurpose this well-tolerated antibody as a targeted delivery vehicle by conjugating it with the emerging radionuclide 161 Tb, which emits low-energy conversion and Auger electrons with ultra-short tissue range, offering high relative biological effectiveness against single tumor cells and micrometastases. However, 161 Tb-based radiopharmaceutical therapy has not been explored in MM. Our purpose is to evaluate the therapeutic potential of [ 161 Tb]Tb-DOTA-Denosumab compared to [ 177 Lu]Lu-DOTA-Denosumab for RANKL-positive MM. Methods DOTA-conjugated Denosumab was labeled with 161 Tb and 177 Lu. Radiochemical purity, in vitro stability and biodistribution were assessed. Therapeutic efficacy was evaluated in U266 and H929 subcutaneous xenograft models. Tumor volume, survival, body weight, hematologic, and biochemical parameters were monitored. Administered-activity-escalation toxicity studies were performed in tumor-free mice. Results Both radiolabeled conjugates showed high radiochemical purity (>95%), excellent in vitro stability and comparable tumor uptake. [ 161 Tb]Tb-DOTA-Denosumab demonstrated significantly enhanced antitumor efficacy compared to [ 177 Lu]Lu-DOTA-Denosumab at equivalent (1.85 MBq) or lower activities. In the U266 model, median survival was prolonged from 33 days (saline) to 45 days with 161 Tb (1.85 MBq) versus 39 days with 177 Lu (1.85 MBq). In the H929 model, median survival extended to 47 days with 161 Tb (1.85 MBq) versus 31 days (saline) and 41 days with 177 Lu (1.85 MBq). Toxicity studies confirmed reversible hematologic changes only at administered activities ≥3.70 MBq, with no severe organ damage. Conclusions This is the first demonstration of 161 Tb-based radiopharmaceutical therapy targeting RANKL in MM. [ 161 Tb]Tb-DOTA-Denosumab exhibits superior antitumor efficacy and prolonged survival compared to its 177 Lu-labeled counterpart. The unique Auger/conversion electron emission of 161 Tb enables potent cytotoxicity against MM cells with favorable organ tolerability. These findings support 161 Tb as a next-generation theranostic radionuclide for RANKL-positive malignancies and provide a strong rationale for clinical translation, highlighting the value of repurposing a clinically established antibody for radiopharmaceutical therapy.