Imaging and radioimmunotherapy of multiple myeloma with anti-idiotypic Nanobodies

Despite the implementation of autologous stem cell transplantation and novel chemotherapeutics, MM remains an incurable cancer due to the regrowth of residual cells. Thus to eliminate MRD, new therapeutic strategies are required. Nanobodies are small, recombinantly produced variable domains of Camelid heavy-chain only antibodies. Due to their favorable biochemical properties, they are valuable tools for molecular imaging and therapeutic purposes. Here we describe, as proof of principle, the generation, characterization and use of anti-idiotypic nanobodies as tools for specific targeting of MM cells in the 5T2MM murine model. After immunizing a dromedary with 5T2MM idiotype (5T2MMid) we identified high-affinity anti-idiotypic nanobodies and demonstrated their specificity in ELISA and FACS assays. Biodistribution studies and SPECT/micro-CT scans using 99mTechnetium-labeled nanobody revealed specific in vivo targeting of the 5T2MMid. Treatment of 5T2MM mice in an MRD-like stage with 177Lutetium-labelled nanobodies targeting specifically MM cells resulted in decreased circulating monoclonal protein (M-protein) and signs of reduced tumor load. Our study shows that anti-idiotypic nanobodies are a new, sensitive, specific and non-invasive tool for imaging and therapeutic purposes and provides a rationale for their clinical evaluation in MM patients.