Background : Autoantibodies play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Plasma cells secrete these autoantibodies but are unfortunately refractory to conventional immunosuppressive treatments. B-cell Maturation Antigen (BCMA) is exclusively expressed on mature B cells and, for that reason, is considered a good target for plasma cell depletion. Here, we analyze a promising therapeutic in development for Multiple Myeloma (MM), that could be used for the treatment for SLE. The antiCD3*BCMA bispecific antibody TNB-383B is in clinical trials for the treatment of MM. In vitro experiment showed that TNB-383B added to human bone marrow samples ex vivo induced a dose dependent lysis of BCMA-expressing plasma cells.
Methods : Depletion of plasma cells by TNB-383B was tested using bone marrow samples extracted from bone retrieved of hip replacments. Human bone marrow mononuclear cells (n=10) were incubated with TNB-383B at increasing concentrations. The activity of TNB-383B was compared to a positive control antibody (PC), which has a BCMA-binding domain and an Fc region identical to TNB-383B, but binds to CD3 with stronger affinity. Bone marrow mononuclear cells were incubated for 18 hours with controls and TNB383B and samples were analyzed for plasma cell depletion (cells expressing CD19+, IgD-, IgM-, CD38++, CD27++) and T cell activation (CD69, CD107a, CD137, CD154). Cytokine production (IFN-, TNF, IL-2, IL-6, IL-12p70, IL-13, IL-4 and IL-10) was evaluated using multiplex.
Results : TNB-383B effectively depleted plasma cells in bone marrow samples of healthy individuals undergoing hip replacement; more than 80% of BCMA expressing plasma cells were depleted after an overnight incubation with TNB-383B or a positive control. Analysis activation markers showed that TNB-383B activated T cells as evidenced by the expression of activation markers (CD69, CD154 or CD137) but only minimal cytokine production was observed.
Conclusions : TNB-383B represents a novel immunotherapeutic with improved safety and efficacy for the treatment of pathogenic long-lived plasma cells. TNB-383B is in clinical trials for the treatment of Multiple Myeloma. TNB-383B could be an attractive treatment to prevent acute organ rejection in Panel Reactive Antibody (PRA) organ transplantation and autoimmune patients including Systemic Lupus Erythematosis. Teneobio anticipates to start testing TNB-383B in PRA patients by late 2019.