B-Cell Maturation Antigen (BCMA) as a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

Abstract

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, has approximately doubled the disease's five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug's effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

Keywords: BCMA; JNJ-68284528; antibody-drug conjugates; belantamab mafodotin; bispecific T-cell engager; chimeric antigen receptor T-cells; idecabtagene vicleucel; myeloma.

Figure 1

BAFF/APRIL/BCMA Axis. Tumor necrosis factor (TNF) family members BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand) are cytokines secreted in the bone marrow microenvironment that play key roles in B cell development, as well as in supporting the viability and proliferation of plasma cells in multiple myeloma. Both BAFF and APRIL serve as ligands for two receptors on the myeloma cell surface—transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA). BAFF also binds to BAFF-R, another myeloma cell receptor. The receptor blockers shown, atacicept, tabalumab, and BION-1301, have been studied in MM patients but have failed to provide evidence of efficacy. On the other hand, inhibitors of BCMA have demonstrated great potential in the therapy of MM. Created with BioRender.com.

Figure 2

The schematic diagram of representative structures of BCMA-targeted chimeric antigen receptors (CAR). The BCMA CARs contain a single- chain of BCMA antibody variable fragment (ScFv), a transmembrane domain, a hinge region, a co-stimulation domain (4-1BB, CD28 or OX40), and a CD3ζ domain. Additional sequences (such as PI3K inhibitor) are added to enhance identification of CAR+ T cells. LCAR-B38M CAR contains two epitopes of BCMA scFv, VHH1 and VHH2. PI3K: phosphoinositol 3-kinase. Adapted from Lin et al. [156] with permission through Copyright Clearance Center, Inc.