The Role of B-Cell Maturation Antigen in the Biology and Management of, and as a Potential Therapeutic Target in, Multiple Myeloma

Abstract

B-cell maturation antigen (BCMA) was originally identified as a cell membrane receptor, expressed exclusively on late stage B-cells and plasma cells (PCs). Investigations of BCMA as a target for therapeutic intervention in multiple myeloma (MM) were initiated in 2007, using cSG1 as a naked antibody (Ab) as well as an Ab-drug conjugate (ADC) targeting BCMA, ultimately leading to ongoing clinical studies for previously treated MM patients. Since then, multiple companies have developed anti-BCMA-directed ADCs. Additionally, there are now three bispecific antibodies in development, which bind to both BCMA and CD3ε on T-cells. This latter binding results in T-cell recruitment and activation, causing target cell lysis. More recently, T-cells have been genetically engineered to recognize BCMA-expressing cells and, in 2013, the first report of anti-BCMA-chimeric antigen receptor T-cells showed that these killed MM cell lines and human MM xenografts in mice. BCMA is also solubilized in the blood (soluble BCMA [sBCMA]) and MM patients with progressive disease have significantly higher sBCMA levels than those responding to treatment. sBCMA circulating in the blood may limit the efficacy of these anti-BCMA-directed therapies. When sBCMA binds to B-cell activating factor (BAFF), BAFF is unable to perform its major biological function of inducing B-cell proliferation and differentiation into Ab-secreting PC. However, the use of γ-secretase inhibitors, which prevent shedding of BCMA from PCs, may improve the efficacy of these BCMA-directed therapies.

BAFF-driven B cell hyperplasia underlies lung disease in common variable immunodeficiency

“…BCMA and TACI may compete for ligand and/or provide signals that regulate the effects of BAFF-R. Thus, deficiency of these 2 receptors may exacerbate BAFF-R-driven survival mechanisms that lead to the B cell hyperplasia underlying CVID ILD (65,66).…”

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

“…BCMA is also expressed at much lower concentrations (9-to 50-fold lower) by plasmacytoid dendritic cells, which are known to help promote MM PC survival in the bone marrow environment [13,17]. Additional details regarding the role of BCMA in B-cell biology and in MM, including illustrations, can be found in other reviews [18][19][20][21].…”

“…For example, one study found that patients with a complete response (CR) had lower sBCMA levels (median, 38.9 ng/mL) than patients with a partial or minimal response (median, 99.7 ng/mL) or nonresponsive disease (median, 195.3 ng/mL) [29]. Because sBCMA has a much shorter serum half-life (24-36 h) compared with Mprotein (3-4 weeks), changes in sBCMA more rapidly reflect changes in disease status than M-protein levels and therefore may serve as a useful alternative and potentially more sensitive marker for monitoring disease status [20,34]. Notably, sBCMA levels do not appear to change more significantly in response to one particular class of anti-MM therapy over others [7].…”

“…It has been demonstrated that sBCMA can bind to and interfere with anti-BCMA antibodies [38]. In this case, drugs that inhibit γsecretase could enhance the efficacy of BCMA-targeted therapy by reducing shedding of BCMA from the cell surface and subsequent interference of BCMA-targeted therapies by sBCMA [20,21,38]. An additional approach could be to use anti-BCMA monoclonal antibodies (mAbs) with higher specificity for membrane-bound BCMA than sBCMA [39].…”

Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma?

“…However, the variable density of BCMA on MM cells in different patients and the propensity of target escape after initial BCMA-targeting immunotherapy may compromise therapeutic efficacy. For example, BCMA on the cell surface can be cleaved by γ-secretase [77], and the resulting reduced cell surface level of BCMA and increased serum level of soluble BCMA could potentially limit the efficacy of BCMA-directed adoptive T-cell therapy by inhibiting CAR T-cell recognition of BCMA on myeloma cells [33,78,79]. Therefore, targeting other members in this ligand-receptor subgroup such as TACI, either alone or in combination with BCMA-targeting therapies, might achieve better clinical efficacy or improve the treatment outcome for MM patients.…”