Principles and current clinical landscape of NK cell engaging bispecific antibody against cancer

Monoclonal antibody-based targeted therapies have greatly improved treatment options for patients by binding to the innate immune system. However, the long-term efficacy of such antibodies is limited by mechanisms of drug resistance. Over the last 50 years, with advances in protein engineering technology, more and more bispecific antibody (bsAb) platforms have been engineered to meet diverse clinical needs. Bispecific NK cell engagers (BiKEs) or tri-specific NK cell engagers (TriKEs) allow for direct targeting of immune cells to tumors, and therefore resistance and serious adverse effects are greatly reduced. Many preclinical and clinical trials are currently underway, depicting the promise of antibody-based natural killer cell engager therapeutics. In this review, we compile worldwide efforts to explore the involvement of NK cells in bispecific antibodies. With a particular emphasis on lessons learned, we focus on preclinical and clinical studies in malignancies and discuss the reasons for the limited success of NK-cell engagers against solid tumors, offering plausible new ideas for curing some advanced cancers shortly.