Dual targeting strategies with bispecific antibodies

Abstract

Monoclonal antibodies are widely used for the treatment of cancer, inflammatory and infectious diseases and other disorders. Most of the marketed antibodies are monospecific and therefore capable of interacting and interfering with a single target. However, complex diseases are often multifactorial in nature, and involve redundant or synergistic action of disease mediators or upregulation of different receptors, including crosstalk between their signaling networks. Consequently, blockade of multiple, different pathological factors and pathways may result in improved therapeutic efficacy. This result can be achieved by combining different drugs, or use of the dual targeting strategies applying bispecific antibodies that have emerged as an alternative to combination therapy. This review discusses the various dual targeting strategies for which bispecific antibodies have been developed and provides an overview of the established bispecific antibody formats.

Keywords: allergic diseases; bispecific antibodies; cancer therapy; dual retargeting; dual targeting; inflammatory diseases.

Figure 1

(A–H) Dual targeting strategies utilizing bispecific antibodies: (A) neutralization of two receptor-activating ligands, (B) neutralization of two receptors, (C) neutralization of a receptor and a ligand, (D) activation of two receptors, (E) activation of a receptor and inactivation of another receptor, (F) activation of a receptor and inactivation of a ligand, (G) blockage of two epitopes of one receptor, (H) blockage of two epitopes of one ligand. (I–O) Dual retargeting strategies utilizing bispecific antibodies: (I) binding to two receptors and Fc-mediated ADCC or CDC, (K) retargeting of cytotoxic effector cells with a trispecific antibody, (L) targeting of a bispecific toxin (immunotoxin) or a bispecific antibody-drug conjugate (ADC) to two receptors, (M) targeting of a bispecific cytokine (immunocytokine) to two receptors, (N) targeting of an enzyme to two receptors, (O) targeting of a drug-loaded nanoparticle/liposome to two receptors. Strategies are exemplified with bispecific IgG and Fab molecules, respectively.

Figure 2

Bispecific antibody formats. Variable heavy chain domains (V_H) are shown in dark blue and dark red, variable light chain domains (V_L) are shown in light blue and light red, red and blue indicating different specificities. Antibody constant domains are shown in white boxes and fusion proteins in white circles.