The therapeutic potential of Actinium-225-labeled CS1-specific single-domain antibodies for the treatment of Multiple Myeloma

Multiple myeloma (MM) is a hematological malignancy characterized by the presence of clonal plasma cells in the bone marrow niche. Despite significant therapeutic advances, MM remains incurable for the majority of patients. This is mainly due to an incomplete eradication of residual cancer cells and/or acquired drug resistance after an effective induction therapy. Targeted radionuclide therapy (TRNT) has emerged as a promising treatment option to eradicate residual cancer cells. We first identified CS1 as potential target for TRNT. CS1 was highly expressed by both dormant and proliferating MM cells, while low expression was observed in environmental cells. CS1 expression remained high during different stages of disease progression and at relapse of MM patients. In this study, we developed and characterized single domain antibodies (sdAbs) against the MM-antigen CS1 and evaluated its therapeutic potential in MM using TRNT. Biodistribution studies demonstrated the specific uptake of anti-CS1 sdAbs in tissues of 5TMM cell infiltration including bone, spleen and liver. TRNT using anti-CS1 sdAbs labeled with actinium-225 significantly prolonged survival of syngeneic, immunocompetent 5T33MM mice. In this proof-of-principle study, we highlight, for the first time, the potential of anti-CS1 radionuclide therapy to target residual MM cells.