Engineering antibodies for dual specificity and enhanced potency

Despite the tremendous success of monoclonal antibodies for human therapeutics, there remain several diseases that escape monospecific IgG antibody-mediated immunotherapy. However, the recent in-depth understanding of antibody structure and function, and significant advances in antibody engineering techniques, have facilitated the development of unnatural bispecific antibodies, which are capable of recruiting more powerful effector cells, retargeting target cells, and blocking two different disease mechanisms simultaneously. Conventionally, bispecific antibodies were generated by the fusion of two different hybridoma cells or chemical coupling of two monospecific antibodies. Recently, however, versatile genetic approaches have been devised to produce more homogenous and correctly assembled bispecific antibodies. To ensure improved efficacy, safety, and efficient manufacturing, a variety of strategies to create bispecific antibody fragments and native IgG-like bispecific antibody formats have been developed and are discussed in this review.