T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity

Abstract

As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.

PD-1/LAG-3 bispecific antibody potentiates T cell activation and increases antitumor efficacy

“…Because of its specificity and bi-function, it has become a research hotspot in the field of antibody engineering and has a broad application prospect in the fields of tumor therapy and autoimmune diseases (34)(35)(36). Compared with the monoclonal antibody, the bispecific antibody has an additional specific antigen-binding site (37), which makes them more specific, more accurate in targeting tumor cells, and less toxic to off-target cells, there are four major advantages of BsAb including (1) BsAb has two antigen-binding sites, which allows them to bridge the tumor cells and immune cells, reorient immune cells, and recruit immune cells to the periphery of tumor cells and enhance the anti-tumor effect (37)(38)(39); (2) BsAb can block/activate two different immune signal pathways downstream at the same time to enhance the cytotoxicity of tumor cells (39); (3) BsAb can bind to two different cell surface antigens and may potentially increase binding specificity and reduce side effects such as off-target (40)(41)(42)(43). ( 4) BsAb offers several benefits in terms of manufacture, preparation, and drug declaration, and it is less expensive than antibody combinations (44,45).…”

Immunotherapeutic progress and application of bispecific antibody in cancer

“…Over the past two decades, tumor immunotherapy has developed into the fourth pillar of cancer treatment in addition to surgery, radiotherapy and chemotherapy ( 110 ). One of the most successful immunotherapy modalities is antibody therapy ( 111 ). Among the 119 clinical and 176 preclinical bsAb projects, there are 99 clinical and 153 preclinical projects for tumor therapy.…”

Bispecific Antibody-Based Immune-Cell Engagers and Their Emerging Therapeutic Targets in Cancer Immunotherapy

“…T-cell engagers are engineered bsAbs that redirect and activate T-cells to induce the robust elimination of poorly immunogenic tumors [ 23 ]. Most T-cell engagers comprise two linked antigen-binding variable fragments (Fvs) that specifically target TAAs and the CD3 unit of the T-cell-receptor (TCR) complex, which thereby engages T-cells to form an immune synapse on the surface of tumor cells [ 24 , 25 ]. Generally, the TCR complex on T-cells directly interacts with antigens that are presented on the major-histocompatibility-complex (MHC) molecules of target T-cells, and this interaction plays a pivotal role in T-cell activation and target T-cell killing [ 26 ].…”