T cell receptors (TCRs) are protein complexes formed by six different polypeptides. The CD3 (cluster of differentiation 3) complex is part of the T-cell receptor (TCR) complex and is composed of two CD3ε, one CD3γ, one CD3δ, and two CD3ζ chains.1,2 CD3 complex ensures signal transduction and plays an important role in T-cell activation.1-3A bispecific antibody approach may allow for binding to targets on malignant cells, while simultaneously binding to CD3 on T cells, inducing activation and cytotoxic activity of T cells enabling lysis of target-expressing malignant cells.1,5
Diagram of the T-cell receptor (TCR) complex.
CD3 bispecific antibodies (bsAb) induce the activation and cytotoxic activity of effector T cells enabling lysis of target-expressing malignant cells1,3,5.
T-cell redirection with bispecific antibodies in which one binding arm recognizes a tumor antigen and the other binding arm recognizes CD3 on T-cells.
CD3 bsAbs in clinical trials either lack an Fc region or contain an engineered Fc domain to minimize interaction with Fc receptors.1,3
A key CD3 bsAb development consideration is a need for a format that either significantly limits or eliminates cyokine release syndrome (CRS), since CRS appears to be dose-limiting in most cases for this class of molecules1
Immunotherapy of cancer with CD3 bsAb is a fast developing field, and multiple TAAs are under evaluation for both hematological and solid tumor malignancies with > 44 different CD3 bs Abs in clinical development.3,5
CD20 (cluster of differentiation 20) on B-cells is a clinically well-validated target that is expressed in a wide variety of B-cell malignancies with limited normal tissue expression beyond B cells.7,8
Survivin, an essential apoptotic-related protein, is an attractive intracellular tumor target expressed in multiple solid and hematological cancers that is readily amenable to TCR-directed therapeutics.4
5T4 (trophoblast glycoprotein, TPBG) is an oncofetal antigen and overexpression of the 5T4 gene in different cell types is characterized by morphological changes, inhibition of cell-cell interaction, E-cadherin downregulation, cytoskeletal disruption, reduced adherence, and increased motility.9
5T4 is a transmembrane tumor antigen expressed in multiple tumors types with limited expression in healthy tissue.10
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