BCMA, a member of the tumor necrosis factor receptor superfamily, member 17 (TNFRSF17), also known as B-cell maturation antigen (CD269), promotes B-cell survival and plays a role in regulating humoral immunity. BCMA is highly expressed in multiple myeloma (MM) and serves as a diagnostic biomarker for MM.

Expression of BCMA

BCMA is preferentially expressed by mature B lymphocytes, with minimal expression in hematopoietic stem cells or non-hematopoietic tissues, and is essential for the survival of long-lived bone marrow plasma cells (PCs) , but not for overall B cell homeostasis. BCMA expression is present in precursor B cells, plasma cells, or late B cells in a variety of hematologic malignancies, such as multiple myeloma (MM), chronic lymphocytic leukemia, acute B-lymphocytic leukemia, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma.

(Data source: Dogan A, et al. Blood Cancer J. 2020)

Structure of BCMA

The TNFRSF17 gene (BCMA gene) located on the short arm of chromosome 16 (16p13.13). It is a type III transmembrane glycoprotein composed of 184 amino acids and comprises an extracellular domain, a transmembrane domain, and an intracellular domain. Its extracellular N-terminus contains a conserved motif of six cysteines and an intracellular tumor necrosis factor receptor-associated factor (TRAF) binding domain, which triggers activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) signaling.

(Data source: Uniprot)

BCMA signaling pathway and regulation:

BCMA has two agonist ligands: proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF), which are primarily secreted paracrine-like in the bone marrow (BM) by stromal cells, osteoclasts, and macrophages. APRIL binds to BCMA with a much higher affinity than BAFF and also binds to TACI, whereas BAFF has a higher selectivity for BAFF -R. Upon ligand binding to BCMA, multiple growth and survival signaling cascades are activated in MM cells, most notably the NF-κβ, RAS/MAPK, and PI3K-PKB/Akt pathways. This leads to the upregulation of anti-apoptotic proteins and the production of cell adhesion molecules, angiogenic factors, and immunosuppressive molecules.

(Data source Yu B, et al. J Hematol Oncol. 2020)

BCMA-targeted therapy strategies

Studies of anti-BCMA antibodies have demonstrated potent cytotoxic activity against MM cells in vitro. A variety of innovative BCMA-targeted therapeutics are in active clinical development, including antibody-drug conjugates (ADCs), CAR-T cells, and bispecific T-cell engagers (BiTEs).

(Data source: Yu B, et al. J Hematol Oncol. 2020)

Bispecific antibodies: BiTE® molecules for multiple myeloma contain one scFv that binds to the CD3ε subunit of the T cell receptor and another that binds to a tumor-specific antigen expressed on malignant cells. This dual binding leads to the formation of a cytolytic synapse between the T cell and the BCMA-expressing cell. Because the formation of the cytolytic synapse is independent of standard antigen recognition and co-stimulation mediated by major histocompatibility complex class I, lysis of the target tumor cell occurs independently of any immune escape mechanisms that the tumor cell may employ to evade detection. Currently approved bispecific BCMA antibodies include elranatamab and teclistamab, both of which are bispecific T cell binders, and many more are still in clinical development.

Antibody-drug conjugates: (ADCs) can enhance targeted tumor killing while sparing normal tissue, thereby minimizing toxicity. With improvements in engineering technology, the latest generation of ADCs can be generated through site-specific conjugation, resulting in a uniform drug-to-antibody ratio and improved circulation stability. Several ADCs have been approved for the clinical treatment of lymphoma and leukemia, and several BCMA antibody-drug conjugates are in clinical development.

(Data source: New Drug Intelligence Database)

Chimeric Antigen Receptor (CAR)-modified T-cell therapy: CAR-T cell therapy is a novel immunotherapy that combines the targeting specificity of mAbs with the cytotoxicity of T cells. The molecular engineering of the next-generation CARs has made CAR-T therapy even more promising. Currently, two BCMA-targeted CAR-T therapies—zevorcabtagene autoleucel and equicabtagene autoleucel—are approved for the treatment of patients with relapsed or refractory multiple myeloma. Numerous other CAR-T cell therapy agents are in clinical trials.

(Data source: New Drug Intelligence Database)