Work

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

Year: 2025

Type: article

Abstract: Background: 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.Methods: A high-affinity anti-BCMA nanobody was labeled with [ 18 F]FPy-pyridine prosthetic group for PET imaging and [ 131 I]I for radioligand therapy.Target expression and in vitro 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 [ 131 I]I-BCMA-Nb (four weekly injections of 7.4 or 18.5 MBq), monitoring tumor burden via bioluminescence imaging and [ 18 F]FDG-PET.Toxicity assessment included body weight monitoring, complete blood counts, biochemical analyses, and histopathological examination.Results: [ 18 F]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 [ 131 I]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.Conclusion: 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.

Source: Theranostics

DOI: 10.7150/thno.126920