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. 2018 Feb;182:161-175.
doi: 10.1016/j.pharmthera.2017.08.005. Epub 2017 Aug 20.

T Cell Engaging Bispecific Antibody (T-BsAb): From Technology to Therapeutics

Free PMC article

T Cell Engaging Bispecific Antibody (T-BsAb): From Technology to Therapeutics

Z Wu et al. Pharmacol Ther. .
Free PMC article


Harnessing the power of the human immune system to treat cancer is the essence of immunotherapy. Monoclonal antibodies engage the innate immune system to destroy targeted cells. For the last 30years, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity have been the main mechanisms of anti-tumor action of unconjugated antibody drugs. Efforts to exploit the potentials of other immune cells, in particular T cells, culminated in the recent approval of two T cell engaging bispecific antibody (T-BsAb) drugs, thereby stimulating new efforts to accelerate similar platforms through preclinical and clinical trials. In this review, we have compiled the worldwide effort in exploring T cell engaging bispecific antibodies. Our special emphasis is on the lessons learned, with the hope to derive insights in this fast evolving field with tremendous clinical potential.

Keywords: Bispecific antibodies; Bivalent CD3 binding; Cancer immunotherapy; Potency of bispecific antibodies; T cell engaging bispecific antibodies; TDCC.

Conflict of interest statement

Conflict of interest statement

Memorial Sloan Kettering Cancer Center and NK Cheung have financial interest in Y-mabs Therapeutics, Inc. and Abpro, Inc.


Figure 1
Figure 1. Different formats of T-BsAbs
The different molecular designs are grouped by the valency of binding to tumor antigen (first number) and the valency of binding to CD3 (second number). For example, 2+1 denotes bivalent tumor antigen binding and monovalent CD3 binding.
Figure 2
Figure 2. Hurdles for T cell-mediated tumor surveillance
Insufficient tumor infiltrating lymphocytes (TILs) (both antigen-specific and antigen-nonspecific) can be caused by: (1) low clonal frequency of tumor specific T cells and depletion of lymphocytes by chemotherapy; (2) denial of T cell entry due to increase in interstitial pressure (abnormal angiogenesis and irregular endothelium) and down-regulation of adhesion molecules on endothelial cells (“anergic” EC), both controlled by soluble factors (e.g. endothelin-1, VEGFα and bFGF) secreted by tumor cells and other immunosuppressive cells present in the tumor microenvironment (TME). Mechanisms used by tumor cells to evade T cell killing mainly consist of: (3) downregulation of MHC and the cognate T-cell receptor (TCR) target (peptide-MHC) on tumor cells and suppression by inhibitory immune checkpoint receptor-ligand interactions (e.g. PD1 with PD-L1/PD-L2, CTLA4 with CD80/CD86); (4) anergy mediated by secreted immunosuppressive molecules (e.g., NO, ROS, arginase, IL-10, TGFβ, IDO); (5) alteration by tumor cells of the metabolic environment making it hypoxic and acidic, which can be detrimental to T cell function. Processes (2)-(5) can be executed by the different cellular components in the TME, such as tumor cells, endothelial cells, regulatory T cells (Treg), tumor associated macrophage (TAM), myeloid derived suppressor cells (MDSC), immature neutrophil and immature DC

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