Cancer therapy with bispecific antibodies: Clinical experience

Abstract

The binding of at least two molecular targets simultaneously with a single bispecific antibody is an attractive concept. The use of bispecific antibodies as possible therapeutic agents for cancer treatment was proposed in the mid-1980s. The design and production of bispecific antibodies using antibody- and/or receptor-based platform technology has improved significantly with advances in the knowledge of molecular manipulations, protein engineering techniques, and the expression of antigens and receptors on healthy and malignant cells. The common strategy for making bispecific antibodies involves combining the variable domains of the desired mAbs into a single bispecific structure. Many different formats of bispecific antibodies have been generated within the research field of bispecific immunotherapeutics, including the chemical heteroconjugation of two complete molecules or fragments of mAbs, quadromas, F(ab')2, diabodies, tandem diabodies and single-chain antibodies. This review describes key modifications in the development of bispecific antibodies that can improve their efficacy and stability, and provides a clinical perspective on the application of bispecific antibodies for the treatment of solid and liquid tumors, including the promises and research limitations of this approach.

Figure 1. Bispecific antibody formats

Genetically engineered antibody fragments or the heteroconjugation of intact antibodies to generate bispecific antibodies (biAbs) in various formats are shown: (A) fragment antigen-binding (Fab) format, (B) quadroma (IgG) formats constructed by fusing two hybridomas secreting antibodies of different specificities, (C) single-chain antibody (scFv [single-chain variable fragment])-based formats, (D) diabody formats or (E) chemical heteroconjugation of two IgG molecules [(IgG)₂] of different antigen specificities. Hetero-F(ab)₂ Heterogeneous fragment antigen-binding, TAA tumor-associated antigen