BCMA is a tumor-associated antigen that is universally present and expressed at higher levels on malignant plasma cells compared with nonmalignant cells2
Watch Dr. Landgren discuss the identification of BCMA as an important target for the development of novel therapies
Hello, I’m Dr Ola Landgren. I'm chief of the Myeloma Division and leader of the Experimental Therapeutics Program at the Sylvester Comprehensive Cancer Center at the University of Miami. I’d like to take a moment to discuss unmet needs in multiple myeloma and the identification of BCMA as an important target for the development of novel therapies.
Recently, there have been many treatment options becoming available in multiple myeloma. Unfortunately, we do not yet have an established curative approach for these patients. For patients who become refractory to existing treatments, new therapies are urgently needed, especially those with the potential to provide deep and durable responses.
B-cell maturation antigen, otherwise known as BCMA, has been identified as an important therapeutic target in multiple myeloma. BCMA is a type III transmembrane glycoprotein within the tumor necrosis factor receptor superfamily. It is a tumor-associated antigen that is universally present in multiple myeloma and is expressed at higher levels on malignant plasma cells compared with normal plasma cells. Research into BCMA has led to the development of several BCMA-directed treatment modalities, both approved and experimental including antibody-drug conjugates, or ADCs, chimeric antigen receptor, or CAR T-cells, and bispecific antibodies.
As our understanding of BCMA continues to advance, I look forward to the potential of these treatment modalities for patients with multiple myeloma and I hope you keep learning more.
Selectively expressed on plasma cells2,3,5:
Associated with disease progression2,6:
BCMA overexpression and activation can upregulate various pathways and enhance expression of genes critical for survival, growth, metastasis, and immunosuppression.
Associated with drug resistance1,5,6:
BCMA overexpression leads to enhanced expression of interleukin 10 (IL-10), programmed death-ligand 1 (PD-L1), and other immune-regulatory genes that are thought to suppress the immune response in the bone marrow microenvironment. Additionally in MM patients, BCMA is found in increased levels on plasmacytoid dendritic cells which promote survival and development of drug resistance in MM cells.
Watch this video to see how BCMA can be an immunotherapeutic target in MM
Narrator: BCMA-directed bispecific antibodies in multiple myeloma.
For patients with multiple myeloma, each relapse after a treatment response has a higher risk of treatment resistance, shorter remission, and lesser response to standard treatments than earlier courses of therapy. New treatments are needed for relapsed and refractory multiple myeloma that counter the mechanisms for treatment resistance, including immune evasion. Bidirectional interplay of immunosuppressive factors between multiple myeloma cells and accessory cells in the tumor microenvironment suppress the immune bone marrow milieu leading to immune exhaustion. Ongoing research is investigating the benefit of therapies targeting multiple myeloma cell-surface antigens on multiple myeloma cells.
The cell-surface proteins CD38, CD138, GPRC5D, SLAMF7, TACI, and BCMA are targets for agents approved or currently under investigation for multiple myeloma.
BCMA, or B-cell maturation antigen, is a transmembrane protein found on normal plasma cells and B lymphocytes. In multiple myeloma cells, BCMA is expressed at higher levels compared with nonmalignant cells. BCMA overexpression in multiple myeloma cells can activate pathways that regulate the expression of genes critical for growth, survival, and immunosuppression. Multiple myeloma cells with high levels of BCMA also express IL-10, PD-L1, and other immune regulatory genes that could suppress the immune response in the bone marrow microenvironment. Currently, 3 treatment classes for targeting BCMA are being explored in multiple myeloma: antibody-drug conjugates, CAR T-cells, and bispecific antibodies.
Bispecific antibodies are monoclonal antibodies that bind to 2 different antigens simultaneously to facilitate cell-to-cell interactions, such as for an antitumor immune response. Bispecific antibodies under investigation in multiple myeloma are engineered to bind CD3 on T-cells and a tumor-associated antigen, such as BCMA. The arms' binding affinity to their respective BCMA and CD3 targets impact the activity of a bispecific antibody. Upon binding, a bispecific antibody draws the cells in close proximity through an interaction that is MHC-independent. Signaling from the resulting immunological synapse activates cytolytic cascades and induces proinflammatory cytokines. Simultaneously, bispecific antibodies may inhibit BCMA activity. This immunotherapeutic approach is currently being investigated in clinical studies for the treatment of multiple myeloma.
ADCs – ADCs are composed of an antibody and a cytotoxic chemotherapy compound. ADCs targeted to BCMA are internalized, leading to release of the toxic payload and inducing selective cell death.
CAR-Ts – T-cells that are genetically modified to express a receptor that binds to a specific tumor-associated antigen. In MM, this is BCMA expressed on myeloma cells. Upon binding, T-cell activation occurs, initiating cellular lysis and myeloma cell death.
BsAbs – Engineered to have dual antigen specificity to facilitate cell-to-cell interactions between T-cells and malignant cells expressing tumor-associated antigens, specifically BCMA in MM.
Download a brochure about BCMA-directed BsAbs
CD=cluster of differentiation; GPRC5D=G-protein coupled receptor family C group 5 member D; MHC=major histocompatibility complex; SLAMF7=signaling lymphocytic activation molecule family member 7; TACI=transmembrane activator and calcium modulation ligand interactor.