Keywords :
Multiple myeloma, radiotherapy, 225Ac, sdAb
Abstract :
[en] Context : Multiple myeloma (MM) is a blood cancer characterized by the accumulation of malignant plasma cells in the bone marrow. While initial treatments reduce tumor cells, they rarely eliminate them completely, leading to relapses. CD38, a protein highly expressed on myeloma cells, serves as a promising target for theranostic agents: compounds enabling both diagnosis and therapy. This study introduces a radiolabeled single-domain antibody (sdAb), 2F8, developed in our lab, targeting CD38(1). This theranostic tool combines early cancer detection and therapy with α-emitter radionuclides (TAT)(2).
Methods: The diagnostic potential of 2F8 was previously demonstrated. Here, 2F8 was conjugated with p-SCN-Bn-DOTA and labeled with therapeutic radiometals: 225Ac (α-emitter) and 177Lu (β-emitter). Radiochemical purity (RCP) was evaluated via radio-iTLC and radio-SEC. The stability over time was assessed by incubating in human serum. Binding and internalization in CD38+ RPMI tumor cells were measured by γ-counting, with parallel experiments performed using non-radiolabeled 2F8 to block binding for a comparative analysis.
Results: DOTA conjugation resulted in an average of 1.8 DOTA molecules per sdAb. Labeling with 100 kBq 225Ac and 200 MBq 177Lu achieved RCPs of over 97% after 30 and 45 minutes of incubation, respectively. Both radioligands maintained stability in human serum with RCPs above 90% after 24 hours, validating the use for the in vivo. CD38 binding affinity was preserved, though internalization was limited. Preclinical studies comparing [225Ac]Ac-DOTA-2F8 with its 177Lu-labelled analogue are planned to assess the benefits of TAT.
Conclusions: The 2F8 sdAb can be effectively labeled with 225Ac, retaining its CD38-binding ability. The specificity of 2F8 combined with the cytotoxicity of α-particles shows promise as a theranostic tool for treating minimal residual MM, potentially reducing relapse risk. This is the first CD38-targeting sdAb labeled with 225Ac for TAT in hematological cancers, offering a new approach to MM treatment.
