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BCMA-DIRECTED BsAbs IN MM: TUMOR-RECOGNIZING IMMUNE ENHANCERS1-6

B-cell maturation antigen (BCMA)-directed bispecific antibodies (BsAbs) may provide a new way forward1,2

BsAbs that are designed to target BCMA and cluster of differentiation CD3 on T-cells simultaneously have the potential to function as tumor-recognizing immune enhancers – they can bring T-cells into close proximity to multiple myeloma (MM) cells, leading to T-cell activation and antitumor response.1-6

Hear from the experts:

Watch Dr. Landgren explain how BCMA-directed BsAbs create an antitumor response

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Hello, I’m Dr Ola Landgren. I'm the 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 share a few insights about BCMA-directed bispecific antibodies, a novel treatment modality for patients with multiple myeloma.

BCMA, also known as B-cell maturation antigen, has been identified as an important therapeutic target in multiple myeloma, leading to clinical research and development of BCMA-directed bispecific antibodies. Bispecific antibodies designed to target BCMA have the potential to function as tumor-recognizing immune enhancers. They can engage BCMA found on myeloma cells and CD3 on T-cells, simultaneously bringing these 2 types of cells into proximity, forming an immune synapse between the T-cell and the myeloma cell.

The formation of this synapse between the T-cell and MM cell leads to T-cell activation. This initiates a cascade in which enzymes such as granzyme and perforin are released, inducing cell lysis. This major histocompatibility complex, or MHC-independent, interaction has been shown to generate a robust T-cell response. This T-cell response activates cytotoxic CD8+ T-cells, as well as regulatory and helper CD4+ T-cells without the need for costimulatory molecules. This independence from costimulatory molecules can help overcome tumor escape mechanisms.

The design and structure of a bispecific antibody may affect the binding affinity to the target and immunogenicity, which could impact patient outcomes. Bispecific antibodies are being investigated for both subcutaneous and intravenous administration and are intended to be administered until disease progression. They could be used as an off-the-shelf option, without the need for patient-specific manufacturing.

I hope you found this brief overview of BCMA-directed bispecific antibodies insightful. As research continues, I am excited to see how bispecific antibodies may offer a new way forward for patients with multiple myeloma.

From immune dysfunction to immune enhancement with T-cell activation2,4,7:

  • Recruitment of cytotoxic T-cells to tumor cells leads to the formation of a cytolytic synapse
  • Upon T-cell activation, cytolytic enzymes such as granzyme B and perforin are released with the ability to induce tumor cell lysis

MHC-independent interaction, which can help overcome tumor escape mechanisms2,4,8,9:

  • Generates a robust T-cell response, engaging cytotoxic CD8+ T-cells as well as regulatory and helper CD4+ T-cells without the need for co-stimulatory molecules

Watch how BCMA-directed BsAbs work as tumor-recognizing immune enhancers

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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.

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.