B-cell maturation antigen (BCMA) is a protein found on the surface of certain immune cells. An antigen is a molecule the immune system can recognize. B-cells, also known as B lymphocytes, are a type of white blood cell that mature in the bone marrow and produce antibodies that fight infections. BCMA is specifically present on mature B-cells, playing a role in their development and function within the immune system.
The Biological Role of BCMA
B-cell maturation antigen (BCMA), also known as Tumor Necrosis Factor Receptor Superfamily Member 17 (TNFRSF17), functions as a receptor protein. It is primarily expressed on plasma cells, which are fully mature B-cells that generate large quantities of antibodies. BCMA binds to specific ligands, such as B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). This binding initiates signaling pathways within the cell, including NF-kappaB and JNK, which are involved in cell survival and proliferation.
The presence of BCMA is important for the survival and long-term maintenance of plasma cells, especially those residing in the bone marrow. BCMA’s interaction with its ligands helps ensure the longevity of these antibody-producing cells. This function is fundamental to the body’s sustained humoral immunity, allowing for continuous antibody production against various pathogens. BCMA’s expression is largely restricted to these late-stage B-cells and plasma cells, with minimal presence on other normal tissues.
BCMA’s Involvement in Disease
BCMA’s role extends beyond normal immune function, becoming implicated in certain diseases. Multiple myeloma, a cancer of plasma cells, is characterized by an abnormally high amount of BCMA on the surface of malignant plasma cells. This overexpression distinguishes cancerous cells from healthy ones, as normal plasma cells express BCMA at lower levels. The increased presence of BCMA on myeloma cells allows them to receive enhanced survival signals from their ligands, BAFF and APRIL, which are also often elevated in patients with the disease.
This amplified signaling through BCMA helps the cancerous plasma cells proliferate excessively and resist natural cell death. The sustained activation of pro-survival pathways, such as AKT, MAPK, and NF-κB, contributes to the aggressive nature of multiple myeloma and its resistance to conventional treatments. BCMA has emerged as a compelling target for therapies, given its widespread and elevated expression on malignant myeloma cells and limited presence on other healthy tissues.
Therapies That Target BCMA
The unique expression of BCMA on multiple myeloma cells has led to the development of several targeted therapies. CAR T-cell therapy involves genetically engineering a patient’s own T-cells. These T-cells are modified in a laboratory to express a chimeric antigen receptor (CAR) on their surface, enabling them to specifically recognize and bind to BCMA on myeloma cells. Once bound, these CAR T-cells become activated, initiating a direct attack that leads to the destruction of the cancer cells.
Antibody-drug conjugates (ADCs) represent another targeted strategy. These therapies consist of an antibody designed to recognize BCMA, linked to a potent cancer-killing drug. When the antibody binds to BCMA on the myeloma cell surface, the entire complex is internalized. Inside the cell, the drug is released, disrupting cellular processes like microtubule formation or causing DNA damage, which ultimately leads to the death of the cancer cell. Belantamab mafodotin is an example of such an ADC, where the drug monomethyl auristatin F (MMAF) is delivered specifically to BCMA-expressing cells.
Bispecific antibodies offer a third therapeutic avenue, acting as a bridge between cancer cells and immune cells. These engineered molecules have two binding arms: one arm attaches to BCMA on the myeloma cell, while the other arm binds to CD3, a protein found on the surface of a patient’s T-cells. By bringing the T-cell into close proximity with the myeloma cell, bispecific antibodies activate the T-cell, redirecting its cytotoxic activity to specifically destroy the cancer cell.
These treatments can lead to side effects, with Cytokine Release Syndrome (CRS) being a notable concern. CRS occurs when activated immune cells release a large number of inflammatory molecules called cytokines into the bloodstream. Symptoms can range from fever and fatigue to more severe manifestations like low blood pressure or breathing difficulties, typically managed with supportive care and immunosuppressive medications. The severity of CRS can correlate with the disease burden, meaning a higher number of cancer cells may lead to a more intense immune response.
Monitoring Treatment Response
After undergoing BCMA-targeted therapy, monitoring treatment response is a crucial step to determine effectiveness and guide ongoing care. Doctors commonly assess disease status through various laboratory tests.
Blood tests are frequently utilized to measure cancer markers, such as monoclonal protein (M-protein) and serum free light chains (sFLCs), which are produced by myeloma cells. A significant reduction or disappearance of these markers often indicates a positive response to therapy.
Bone marrow biopsies are also performed to directly examine the bone marrow for the presence and quantity of myeloma cells. This procedure involves collecting a small sample of bone marrow, usually from the hip bone, to assess the percentage of malignant plasma cells. A decrease in these cancerous cells within the bone marrow signifies a reduction in disease burden. For patients with “non-secretory” myeloma, where M-protein levels are not measurable, bone marrow biopsies or sFLC tests can be particularly useful for monitoring.
Imaging scans, such as X-rays, MRI, CT scans, or PET scans, may be used to identify bone lesions often associated with multiple myeloma. These scans help in understanding the extent of bone involvement and can show improvements or stability in response to treatment.