Precision radiolabeled B-cell maturation nanobody for targeted PET imaging and radioligand therapy of disseminated multiple myeloma

<b>Background:</b> Multiple myeloma (MM) is an incurable plasma cell malignancy with limited disease-specific imaging options. Current diagnostic methods often fail to detect early disease states and minimal residual disease, highlighting the need for more precise molecular imaging and targeted therapeutic approaches. We developed a radiolabeled nanobody targeting B-cell maturation antigen (BCMA) to enable both high-contrast molecular imaging and targeted radioligand therapy in human MM models. <b>Methods:</b> A high-affinity anti-BCMA nanobody was labeled with [¹⁸F]FPy-pyridine prosthetic group for PET imaging and [¹³¹I]I for radioligand therapy. Target expression and <i>in vitro</i> binding affinity and specificity were assessed using biolayer interferometry, flow cytometry, and cell-based assays. PET imaging studies were performed in subcutaneous MC38-human BCMA xenografts and systemic human MM models (H929 and RPMI8226 cell lines) administered intravenously in NSG mice. Therapeutic efficacy was evaluated using a fractionated treatment regimen with [¹³¹I]I-BCMA-Nb (four weekly injections of 7.4 or 18.5 MBq), monitoring tumor burden via bioluminescence imaging and [¹⁸F]FDG-PET. Toxicity assessment included body weight monitoring, complete blood counts, biochemical analyses, and histopathological examination. <b>Results:</b> [¹⁸F]FPy-BCMA-Nb demonstrated high binding affinity and excellent tumor specificity with rapid systemic clearance. PET imaging showed significantly higher uptake in BCMA-positive lesions (6-8% ID/g) compared to controls (1% ID/g), with minimal kidney retention (<1% ID/g by 3 h). In systemic MM models, the tracer specifically targeted bone marrow lesions with high tumor-to-background ratios. Therapeutic studies revealed dose-dependent tumor regression, with the 18.5 MBq [¹³¹I]I-BCMA-Nb regimen achieving 100% complete remission in treated mice. Biochemical and histopathological analyses confirmed minimal systemic toxicity, restoration of normal hematopoiesis, and significant reduction in BCMA expression and proliferation markers post-treatment. <b>Conclusion:</b> This BCMA-targeted nanobody platform offers a promising theranostic approach for precise detection and treatment of disseminated multiple myeloma. The combination of exceptional tumor specificity, minimal off-target accumulation, rapid clearance, and potent therapeutic efficacy, along with a favorable safety profile, supports its potential for clinical translation in MM diagnosis and therapy.