Antibody-based BCMA targeted theranostics of multiple myeloma

• Applicants: Privatdozent Dr. Dirk Hose; Professor Dr. Jens Pietzsch; Dr. Anja Seckinger
• Subject Area: Hematology, Oncology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2020 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429647811

Multiple myeloma is a rarely curable malignant hematological disease characterized by the accumulation of clonal plasma cells in the bone marrow. With more than 80,000 new diagnoses worldwide per year, myeloma is the second most common hematological malignancy. Median survival after intensive treatment including high-dose chemotherapy followed by autologous stem cell transplantation is currently 8-9 years. Novel treatment concepts allow higher response rates as well as deeper remissions and in one third of these patients, no more myeloma cells can be detected. With current techniques, i.e. next generation flow cytometry (NGF) and next generation sequencing (NGS), absence of detectable disease in myeloma patients however does not imply absence of residual tumor cells and also patients without detectable myeloma cells at the site of bone marrow aspiration show disease progression and relapse. This in turn necessitates simultaneous use of whole-body imaging techniques, e.g. combined positron-emission tomography-computed tomography (PET-CT) or whole-body magnetic resonance imaging (WB-MRI). Both WB-MRI and PET-CT are far less sensitive than NGF or NGS. Main reason is lack of specific and sensitive tracers against target structures on (malignant) plasma cells. Within previous work, we identified B-cell maturation antigen (BCMA) as excellent highly expressed target. We could show that BCMA is expressed on myeloma cells from all patients investigated, including those with highly proliferative disease or high risk patients regarding chromosomal aberrations or gene expression-based risk scores. In contrast, it is not expressed on any of the other cellular populations within the bone marrow microenvironment except normal and malignant plasma cells. As BCMA expression is absent in early B-cell development, i.e. memory B-cells, this allows for a rapid re-emergence of B-cell immunity after cessation of anti-BCMA treatment. Due to the restricted expression, BCMA is thus an “ideal” target structure for the development of tracers or therapeutic radiopharmaceuticals in virtually all patients with multiple myeloma.Aim of our project is the development of an antibody-based BCMA-targeted (anti-BCMA) theranostics of multiple myeloma by first a diagnostic 64Cu-anti-BCMA PET-tracer for functional molecular imaging (localization, functional expression of BCMA and quantification) of residual tumor cells and, secondly, a therapeutic 67Cu-anti-BCMA radiopharmaceutical especially for treatment of patients with residual disease. The clinical significance is threefold: i) Response assessment (=number of residual myeloma cells) per se after successful systemic treatment and ii) prognostication, as deeper remissions are associated with longer progression-free and overall survival, using the diagnostic 64Cu-anti-BCMA PET-tracer, as well as iii) guiding of treatment, e.g. using the therapeutic 67Cu-anti-BCMA radiopharmaceutical.

• DFG Programme: Research Grants