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, 9, 1821

Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy


Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

Shih-Feng Cho et al. Front Immunol.


The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed at significantly higher levels in all patient MM cells but not on other normal tissues except normal plasma cells. Importantly, it is an antigen targeted by chimeric antigen receptor (CAR) T-cells, which have already shown significant clinical activities in patients with RRMM who have undergone at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Moreover, the first anti-BCMA antibody-drug conjugate also has achieved significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. Both BCMA targeting immunotherapies were granted breakthrough status for patients with RRMM by FDA in Nov 2017. Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.

Keywords: B-cell maturation antigen; bi-specific antibody; chimeric antigen receptor T cell; monoclonal antibody; monoclonal antibody drug conjugate; multiple myeloma; targeted immunotherapy.


Figure 1
Figure 1
Biological significance of B cell maturation antigen (BCMA) in plasma cells (PCs). (A) BCMA is selectively induced during PC differentiation, associated with loss of BAFF-R. It is expressed on late-stage B-cells, short-lived proliferating plasmablasts, and long-lived PCs. BCMA does not maintain normal B-cell homeostasis but is required for the survival of long-lived PCs. In multiple myeloma (MM), expression of BCMA is significantly increased on malignant vs normal PCs. (B) A proliferation-inducing ligand (APRIL) and BAFF are two natural ligands for BCMA. Specifically, APRIL binds to BCMA with a significantly higher affinity than BAFF. Activation of BCMA supports growth and survival of PCs via activating MEK/ERK, AKT, NFκB, JNK, p38 kinase, and Elk-1. In MM cells, overexpression of BCMA or binding of APRIL to BCMA activates AKT, ERK1/2, and NFκB pathways and upregulate antiapoptotic proteins, i.e., Mcl-1, Bcl-2, Bcl-xL to protect MM cells from dexamethasone- and interleukin-6 deprivation induced apoptosis. Furthermore, BCMA upregulates genes associated with activation of osteoclast, adhesion, and angiogenesis/metastasis. Moreover, overexpressed BCMA can induce the expression immunosuppressive molecules such as PD-L1 in MM cells. Membrane BCMA can be cleaved by γ-secretase, resulting in reduced number of membrane-bound BCMA molecules and increased soluble BCMA. Soluble BCMA can bind to APRIL and BAFF, which may interfere downstream BCMA signaling cascades. TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor; GC, germinal center.
Figure 2
Figure 2
B cell maturation antigen (BCMA)-based immunotherapies with multiple mechanisms of action against MM cells. Various BCMA-based treatment modalities are under clinical development are listed in Table 1 and shown here. BCMA-NK Bi or Tri Ab, not shown here, can also specifically induce effector cell-mediated lysis of MM cells. ADC, antibody drug conjugate; Bi, bispecific full-length immunoglobulin; BiTE, bispecific T-cell engager; CAR T, chimeric antigen receptor T cell; MM, multiple myeloma cell; NK, natural killer cell; Mϕ, macrophage.

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