Bispecific T-cell engagers for cancer immunotherapy

Abstract

Bispecific T-cell engagers (BiTEs) are a new class of immunotherapeutic molecules intended for the treatment of cancer. These molecules enhance the patient's immune response to tumors by retargeting T cells to tumor cells. BiTEs are constructed of two single-chain variable fragments (scFv) connected in tandem by a flexible linker. One scFv binds to a T-cell-specific molecule, usually CD3, whereas the second scFv binds to a tumor-associated antigen. This structure and specificity allows a BiTE to physically link a T cell to a tumor cell, ultimately stimulating T-cell activation, tumor killing and cytokine production. BiTEs have been developed, which target several tumor-associated antigens, for a variety of both hematological and solid tumors. Several BiTEs are currently in clinical trials for their therapeutic efficacy and safety. This review examines the salient structural and functional features of BiTEs, as well as the current state of their clinical and preclinical development.

Figure 1

Overall BiTE structure. (A) Bispecific antibodies can take a variety of formats, which vary in size and complexity. Triomabs are full sized antibodies generated from the fusion of two hybridomas. Fab₂ consist of two unique antigen full Fab binding fragments, which are physically linked together. Diabodies and tandem single chain variable fragments utilize only variable fragments to bind cognate antigens. Diabodies and tandem scFvs differ in how the heavy and light chains are connected to one another, with diabodies linking heavy and light chains from opposing Fvs while tandem scFvs connect heavy and light chains linearly as a single molecule. (B) Layout of a tandem scFv. The heavy and light chains of the two Fvs are linked by short serine-glycine linkers. This linkage results in the formation of a single polypeptide that incorporates both Fvs. (C) Bispecific T cell engager. A bispecific T cell engager (BiTE) is a type of tandem scFv in which one scFv is capable of binding to a T cell. Often, this scFv recognizes the CD3 subunit of the T cell receptor. The second scFv binds to an antigen on tumor cells.

Figure 2

Activation of T cells by BiTEs. To induce activation of and cytotoxic activity by a T cell, a BiTE protein must engage both a T cell and a tumor cell simultaneously, so single cell binding to a T cell or a tumor cell causes no activation. Simultaneous binding of multiple BiTE molecules to both T cell and tumor cell promotes the formation of an immunological synapse leading to T cell activation and release of cytokines and cytotoxicity of the tumor cell.