Bispecific and multispecific antibodies in oncology: opportunities and challenges

Research into bispecific antibodies, which are designed to simultaneously bind two antigens or epitopes, has advanced enormously over the past two decades. Owing to advances in protein engineering technologies and considerable preclinical research efforts, bispecific antibodies are constantly being developed and optimized to improve their efficacy and to mitigate toxicity. To date, >200 of these agents, the majority of which are bispecific immune cell engagers, are in either preclinical or clinical evaluation. In this Review, we discuss the role of bispecific antibodies in patients with cancer, including history and development, as well as innovative targeting strategies, clinical applications, and adverse events. We also discuss novel alternative bispecific antibody constructs, such as those targeting two antigens expressed by tumour cells or cells located in the tumour microenvironment. Finally, we consider future research directions in this rapidly evolving field, including innovative antibody engineering strategies, which might enable more effective delivery, overcome resistance, and thus optimize clinical outcomes. Following the introduction of blinatumomab in 2014, the past 4 years have seen the approval of a further ten bispecific antibodies, reflecting substantial research effort and clinical interest in these agents. In this Review, the authors describe the developments leading to the approval of these novel agents and highlight important future research directions, including clinical optimization as well as innovative antibody engineering approaches.