Overview of Bispecific T-cell Engager

What is Bispecific T Cell Engager

Bispecific T cell engager is a novel immunotherapeutic molecule that can redirect T cells to tumor cell surface antigens, thereby inducing tumor cell lysis. bispecific T cell engager consists of two single-chain variable fragments (scFv), one of which can bind to the CD3 molecule on T cells, and the other can bind to a specific antigen on tumor cells. bispecific T cell engager mediates the close proximity and activation of T cells and tumor cells through this bispecific binding, independent of major histocompatibility complex (MHC) presentation. The concept of bispecific T cell engager was first proposed by Neri et al. in 1997, who linked two scFv by a long peptide chain to form a bispecific antibody (bsAb), and demonstrated its efficacy in killing lymphoma cells targeting CD30 and CD3. Subsequently, Staerz et al. invented a more simplified bsAb structure in 2000, namely bispecific T cell engager, which only contains two scFv and a short peptide linker, thus improving its stability and bioavailability. Since then, bispecific T cell engager has become a popular cancer immunotherapy strategy, attracting widespread attention and research.

Structural Features and Design Principles of Bispecific T Cell Engager

The basic structure of bispecific T cell engager is composed of two scFv connected by a short peptide linker, one of which can bind to the CD3 molecule on T cells, and the other can bind to a specific antigen on tumor cells. This structure gives bispecific T cell engager bispecificity, that is, it can simultaneously recognize T cells and tumor cells, and bring them closer to each other, thereby activating the killing function of T cells.

Fig.1 The construction of bispecific T cell engager. (Wang Q, 2019)

The design principles of bispecific T cell engager mainly include the following points: (1) selecting suitable antigen targets, which require high expression on tumor cells and low or no expression on normal cells, to improve the specificity and sensitivity of bispecific T cell engager; (2) selecting suitable scFv, which require high affinity, high stability, low immunogenicity, and effective binding to CD3 and antigen; (3) selecting suitable linkers, which require sufficient length and flexibility to ensure that there is no interference or folding between the two scFv; (4) selecting suitable expression systems, which require efficient production of bispecific T cell engager molecules with correct conformation and function.

Clinic Status of Bispecific T Cell Engager

Bispecific T cell engager, as a novel cancer immunotherapy strategy, has achieved some encouraging results in clinical trials, especially in hematological malignancies. So far, there is only one bispecific T cell engager, blinatumomab, that has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL) and minimal residual disease (MRD)-positive B-ALL. In addition, there are many other bispecific T cell engagers in different stages of clinical trials, targeting different types of tumors, including hematological malignancies and solid tumors. Below, we will introduce the clinical data of the approved and the clinical trial stage bispecific T cell engagers respectively, and analyze and summarize the data.

Fig.2 The mechanism of Blinatumomab treatment. (Wang Q, 2019)

The only approved bispecific T cell engager so far is blinatumomab, which is a first-generation bispecific T cell engager that can simultaneously bind to CD3 on T cells and CD19 on B cells, and induce T cell-mediated killing of CD19-positive B cell tumors. Blinatumomab was initially granted accelerated approval by the FDA in 2014 for the treatment of patients with relapsed or refractory B-ALL. In addition to adult patients, blinatumomab also showed good efficacy and safety in children and adolescents. It is worth noting that blinatumomab is the first and only targeted immunotherapy drug approved for the treatment of MRD-positive B-ALL patients. MRD refers to a very small number of leukemia cells that still exist in the bone marrow after chemotherapy, which is an important indicator for predicting B-ALL relapse risk and prognosis. In summary, blinatumomab, as an innovative bispecific T cell engager immunotherapy drug, has shown remarkable effects and controllable toxicity in the treatment of B-ALL, opening up a new field for cancer immunotherapy.

In addition to blinatumomab, there are many other types of bispecific T cell engagers in different stages of clinical trials, targeting different types of tumors, including hematological malignancies and solid tumors.

References

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