BCMA-CS1 HLE BiTE Molecule: A Dual-Targeting Strategy for Multiple Myeloma Treatment

Multiple myeloma (MM), a malignant condition affecting plasma cells, is often lethal due to disease recurrence and resistance to treatment, necessitating more effective therapeutic approaches. Immunotherapy, particularly through the use of BiTE (Bispecific T Cell Engager) molecules, has demonstrated potential in targeting MM by directing T cells to destroy tumor cells. These agents bind to both a tumor-associated antigen (TAA) on cancer cells and CD3ε on T cells.

In MM, B-cell maturation antigen (BCMA) is a promising target for TAA due to its widespread presence and limited expression in normal tissues, primarily in plasma cells and plasmablasts. However, challenges arise from variable BCMA expression in cancer cells, the risk of antigen loss, and elevated levels of soluble BCMA in patient serum, which may hinder the effectiveness of BCMA-targeted therapies.

To overcome these obstacles, a novel BiTE molecule has been developed that targets both BCMA and a second TAA, CS1 (SLAMF7), and includes an Fc domain for half-life extension (HLE). This molecule has shown high affinity for human BCMA, CS1, and CD3ε, as well as for non-human primate (NHP) counterparts. In vitro studies revealed its effectiveness against MM cell lines with varying BCMA and CS1 expression levels in a T cell-dependent manner, even in the presence of high concentrations of soluble BCMA.

In vivo studies using a MM xenograft model demonstrated the molecule's ability to inhibit tumor growth. NHP trials over 15 days showed typical BiTE molecule activity, such as transient lymphocyte count fluctuations and cytokine increases. Analyzing bone marrow and blood samples from NHPs using droplet digital PCR (ddPCR) indicated significant reductions in plasma cell-specific transcripts, suggesting effective plasma cell depletion.

Furthermore, the broad expression of CS1 in MM patient samples and its limited presence in a few normal hematopoietic cells suggest that the BCMA-CS1 HLE BiTE molecule could offer significant therapeutic advantages by targeting a wider range of MM cancer cells and overcoming limitations associated with BCMA-specific therapies.