Inhibition of BCMA signaling alters protein translation and Multiple Myeloma growth

Abstract

ABSTRACTB-cell maturation antigen (BCMA) expression is highly expressed on the surface of MM cells and has been used to target MM tumor cells by CAR-T, Antibody-Drug-Conjugates (ADCs) and BCMA-CD3 bispecific antibodies. However, BCMA is critical for the viability of Multiple Myeloma (MM) tumor cells and to date there have not been any effective therapeutics developed to inhibit BCMA signaling. Here, we investigated the potential of using a soluble BCMA decoy receptor fusion protein (sBCMA-Fc) to trap the BCMA ligands, APRIL and BAFF to achieve ligand mediated BCMA signaling inhibition. Treatment with sBCMA-Fc has proven to be safe and efficacious in inhibiting tumor progression in numerous in vivo and syngeneic PDX tumors model. Mechanistically, global ribosome profiling analysis revealed a decrease in the translation efficiency of a subset of proteins in MM cells as a result of BCMA inhibition, indicating that increased BCMA signaling is a driver of dysregulated protein translation in MM cells. In particular, BCMA regulates the translation of ATM interactor (ATMIN/ACSIZ), and inhibition of ATMIN alone reduces the growth of MM cells, supporting its role as a downstream effector of BCMA in promoting MM expansion. Overall, our preclinical and mechanistic data support the concept that inhibition of BCMA signaling through sBCMA-Fc is a viable clinical strategy that alters the protein translation of a subset of proteins that are needed for MM viability and growth.