What Are T Cell Bispecific Antibodies?

The immune system uses T cells and antibodies to defend against disease. T cells are white blood cells that orchestrate immune responses and destroy abnormal cells by recognizing molecules called antigens on their surface. Antibodies are proteins that latch onto foreign substances like bacteria and viruses, marking them for destruction.

Scientists have engineered molecules known as T cell bispecific antibodies, which are laboratory-created proteins that bind to two different targets simultaneously. One part of the antibody attaches to a T cell and the other part attaches to a cancer cell. This dual-binding capability forms a bridge between the immune cell and its target, redirecting a patient’s own T cells to eliminate cancer.

How T Cell Bispecific Antibodies Work

The effectiveness of these antibodies lies in their dual-targeting structure. One arm of the molecule is engineered to bind to a protein on the surface of T cells, most commonly the CD3 receptor. Engaging this receptor, which is part of the T cell’s activation machinery, provides an “on” signal.

The other arm is designed with high specificity for an antigen on the surface of cancer cells, such as CD19 on B-cell lymphomas. This dual-binding function creates a physical bridge between the T cell and the cancer cell. The antibody acts as a molecular matchmaker, allowing the T cell to kill cancer cells it might not otherwise recognize and circumventing some cancer evasion tactics.

Once the T cell is activated through this artificial bridge, it unleashes its cell-killing machinery. The T cell releases cytotoxic substances, such as perforins and granzymes, directly into the connected cancer cell. Perforins create pores in the target cell’s membrane, allowing granzymes to enter and initiate a process called apoptosis, or programmed cell death. This directed attack destroys the cancer cell, and the T cell can then detach to target another.

Diseases Treated with T Cell Bispecific Antibodies

The primary application for T cell bispecific antibodies is in oncology, where they are used to treat various hematological malignancies, or blood cancers. These therapies have become an option for patients whose disease has returned (relapsed) or has not responded to other treatments (refractory). This provides a new avenue for individuals who may have exhausted standard therapies like chemotherapy.

For B-cell lymphomas like Diffuse Large B-cell Lymphoma (DLBCL), antibodies target the CD20 antigen on cancer cells. For B-cell acute lymphoblastic leukemia (ALL), those targeting the CD19 antigen have proven effective. In treating multiple myeloma, a cancer of plasma cells, therapies targeting the B-cell maturation antigen (BCMA) have shown promising results.

Approved T cell bispecific antibodies include blinatumomab (targeting CD19 for ALL) and mosunetuzumab (targeting CD20 for follicular lymphoma). For multiple myeloma, drugs like teclistamab and talquetamab target BCMA and GPRC5D, respectively. These treatments use specific surface proteins on cancer cells to direct the immune system’s attack.

While most established for blood cancers, research is exploring their use for solid tumors. Treating solid tumors is more challenging due to the dense tumor microenvironment and a lack of unique target antigens. Clinical trials are underway for cancers like small cell lung cancer and prostate cancer to identify effective targets. For instance, tarlatamab, which targets the DLL3 protein, was approved for extensive-stage small cell lung cancer.

Understanding and Managing Side Effects

Because these antibodies stimulate the immune system, they can cause side effects from the widespread activation of T cells. A common reaction is Cytokine Release Syndrome (CRS), an inflammatory response caused by a massive release of signaling molecules called cytokines. Symptoms can range from mild to life-threatening and are managed with supportive care and immune-dampening medications like tocilizumab.

CRS symptoms can include:

• High fever
• Fatigue
• Headache
• Muscle pain
• Low blood pressure
• Difficulty breathing

Another serious potential side effect is Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). This condition involves neurological symptoms that arise from inflammation in the central nervous system. Management of ICANS involves high-dose corticosteroids to reduce inflammation in the brain.

Patients with ICANS may experience:

• Confusion or delirium
• Difficulty speaking
• Loss of coordination
• Seizures

Other side effects include infusion-related reactions and cytopenias, which are low blood cell counts. The risk of infection can also increase if the therapy affects healthy B cells. To manage these risks, patients often receive their first doses in a hospital for close monitoring of CRS, ICANS, or other complications.

The Evolving Landscape of T Cell Bispecific Antibodies

The field of T cell bispecific antibodies is evolving, with research focused on enhancing their effectiveness and safety. Scientists are engineering new molecular formats to improve how these drugs perform, aiming to extend their half-life for less frequent dosing. Other modifications fine-tune their binding affinities to reduce toxicity while maintaining anti-tumor activity.

A major area of development is identifying new targets on cancer and T cells to apply this approach to more cancers, including solid tumors. The search for antigens highly expressed on cancer cells but absent from healthy tissues is a focus, as this would minimize side effects.

Researchers are exploring using T cell bispecific antibodies with other cancer treatments, like checkpoint inhibitors or chemotherapy. This could create a multi-pronged attack against cancer. Combination strategies are being investigated in clinical trials to determine the most effective and safe pairings for different cancers.

One advantage of these therapies is their “off-the-shelf” nature. Unlike personalized cell therapies like CAR-T, which require manufacturing a patient’s own cells, bispecific antibodies are standardized medicines ready for immediate use. This makes them more accessible and simplifies the treatment process, and the development pipeline for new bispecifics continues to grow.