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Review
. 2016 Dec 28;18(1):48.
doi: 10.3390/ijms18010048.

Bispecific Antibodies as a Development Platform for New Concepts and Treatment Strategies

Fa Yang  1 , Weihong Wen  2 , Weijun Qin  3
Affiliations
Review

Bispecific Antibodies as a Development Platform for New Concepts and Treatment Strategies

Fa Yang et al. Int J Mol Sci. .

Abstract

With the development of molecular cloning technology and the deep understanding of antibody engineering, there are diverse bispecific antibody formats from which to choose to pursue the optimal biological activity and clinical purpose. The single-chain-based bispecific antibodies usually bridge tumor cells with immune cells and form an immunological synapse because of their relatively small size. Bispecific antibodies in the IgG format include asymmetric bispecific antibodies and homodimerized bispecific antibodies, all of which have an extended blood half-life and their own crystalline fragment (Fc)-mediated functions. Besides retargeting effector cells to the site of cancer, new applications were established for bispecific antibodies. Bispecific antibodies that can simultaneously bind to cell surface antigens and payloads are a very ideal delivery system for therapeutic use. Bispecific antibodies that can inhibit two correlated signaling molecules at the same time can be developed to overcome inherent or acquired resistance and to be more efficient angiogenesis inhibitors. Bispecific antibodies can also be used to treat hemophilia A by mimicking the function of factor VIII. Bispecific antibodies also have broad application prospects in bone disorders and infections and diseases of the central nervous system. The latest developments of the formats and application of bispecific antibodies will be reviewed. Furthermore, the challenges and perspectives are summarized in this review.

Keywords: angiogenesis inhibitors; bispecific T cell engagers (BiTEs); bispecific antibodies; delivery system; drug resistance; immunological synapse; immunotherapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Single-chain-based formats. (A) The structure of BiTEs. The two linkers outside the chain are about 15 amino acids (G4S1)3, which is sufficiently long and flexible to make light chains and heavy chains form the right conformation; (B) The structure of dual-affinity re-targeting proteins (DARTs). The linker between heavy and light chains is as short as about five amino acids. Because of the short linker between the two domains of scFv, the two domains of the same scFv cannot pair and are forced to homodimerize with its homologous partner in another scFv. The adding of another cysteine residue at the end of VHA and VHB is helpful for the stability of this kind of bispecific antibody by forming a disulfide linkage; (C) The structure of Tandem diabodies (TandAbs). The three linkers of TandAb are all short linkers; it is hard to pair within the chain while easy to dimerize between two chains and generate.
Figure 2
Figure 2
IgG-based formats. (A) The structure of Fc and its binding ligands. Dark arrows mark the binding site of different binding ligands; (B) The formation of quadroma cells to produce rat/mouse bispecific antibodies; (C) “Knobs-an-holes” and charge pairing technology solving the heavy chain mispairing problem; (D) The common light chain technology solving the light chain mispairing problem; (E) The three formats of crossmab, the exchange of VHB and VLB, the exchange of CH1 and CLB and the exchange of VHB-CH1 and VLB-CLB; (F) The format of double-variable domain (DVD)-Ig; (G) The format of S-Fab; (H) The format of Fv-Fc.
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