BCMA-targeted immunotherapy for multiple myeloma

Abstract

B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development.

Keywords: Antibody-drug conjugate; B cell maturation antigen; BCMA; Belantamab mafodotin; Bispecific T cell engager; CAR-T.

Fig. 1

BCMA gene and protein. BCMA is encoded by the TNFRSF17 gene (BCMA gene) located on the short arm of chromosome 16 (16p13.13). The BCMA gene comprised of 3 exons separated by 2 introns. BCMA is a type III transmembrane glycoprotein, with an extracellular N terminus containing a conserved motif of 6 cysteines and an intracellular tumor necrosis factor receptor-associated factor (TRAF) binding domain that triggers the activation of nuclear factor κ-light-chain enhancer of activated B cells (NF-κβ) signaling

Fig. 2.

BCMA signaling pathway. BCMA has two agonist ligands: a proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF), which are mainly secreted by the bone marrow (BM) stromal cells, osteoclasts, and macrophages in a paracrine manner in the BM. APRIL exhibits a much higher binding affinity to BCMA than BAFF, and it also binds to TACI, while BAFF endorses more selectivity to BAFF-R. Multiple growth and survival signaling cascades are subsequently activated in the multiple myeloma (MM) cells, most frequently through NF-κβ, leading to upregulation of anti-apoptotic proteins and production of cell adhesion molecules, angiogenesis factors, and immunosuppressive molecules. These lead to increased survival of MM cells. Membrane BCMA can be cleaved by γ-secretase and released to the plasma as soluble BCMA (sBCMA). sBCMA can bind to APRIL and BAFF, which may interfere with the activation of BCMA signaling pathways

Fig. 3

BCMA-targeted immunotherapies. a Antibody-drug conjugate (ADC). Upon binding to BCMA on the surface of multiple myeloma (MM) cells, ADC is internalized first and the linker is hydrolyzed inside of the lysosomes or endosomes, releasing the payloads that lead to cell death. b Chimeric antigen receptor (CAR)-T cells. The ectodomain of the BCMA scFv on the CAR-T cells binds to BCMA on the surface of MM cells. This leads to activation of the CAR-T cells which release cytotoxic cytokines and cause MM cell death. c Bispecific T cell engager (BiTE). The dual BCMA- and CD3-scFv-containing BiTE binds concomitantly to CD3 and BCMA, facilitating T cell/MM cell crosslinking, followed by CD4⁺/CD8⁺ T cell activation and secretion of cytotoxic cytokines, leading to MM cell death