Development of a New BCMAxCD3 Duobody® Antibody for Multiple Myeloma

B-cell maturation antigen (BCMA) is a tumor necrosis factor (TNF) family surface protein predominantly expressed on terminally differentiated B-cells. BCMA signals through P38/NF-κB pathway upon binding to its ligands; a proliferation inducing ligand (APRIL) and B-cell activator of the TNF family (BAFF) and promote anti-apoptotic gene expression. BCMA expression is elevated in plasma blasts, plasma cells from spleen and bone marrow and correlates with disease progression in multiple myeloma (MM). BCMA expression in premalignant MM settings such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) also gives an opportunity for early cancer interception. To target cancer cells expressing BCMA, we developed a BCMAxCD3 bispecific antibody using the Genmab DuoBody® technology (Ab-957) to recruit T cells to BCMA-expressing MM cells so that T cells could be activated and induced to kill BCMA⁺ cancer cells. This antibody can induce cytotoxicity of BCMA⁺ MM cell lines in vitro (H929 cells: EC₅₀=0.15nM, MM1.R cells: EC₅₀=0.06nM, RPMI8226 cells: EC₅₀=0.45nM) with a concomitant T cell activation (H929 cells: EC₅₀=0.21nM, MM1.R cells: EC₅₀=0.1nM, RPMI8226 cells: EC₅₀=0.28nM). In contrast, this antibody was unable to kill BCMA^- cancer cell line (MV4-11), demonstrating the specificity of the cytotoxicity. Ab-957 also inhibited tumor development or growth in two BCMA⁺ MM murine xenograft models inoculated with human T cells. Furthermore, this antibody could deplete BCMA⁺ cells in bone marrow samples from MM patient's in an ex-vivo assay with an average EC₅₀ value of 2.5 nM. Lastly, Ab-957 is well-tolerated in cynomolgus monkey and is being developed for Phase I clinical trial in patients with multiple myeloma.