Advances in bispecific biotherapeutics for the treatment of cancer.

Conventional monoclonal antibody (mAb) therapeutics interfering with cellular signaling of their respective target antigens are frequently limited in their ability to induce significant anti-tumor activities when administered as single agents in patients with solid tumors. To overcome these limitations, several new technologies are being developed to empower biotherapeutics and to improve their anti-tumor activities, while maintaining their high tumor selectivity and superior safety profiles. The various efficacy enhancement technologies developed for mAbs can be divided broadly into two categories: First, technologies that improve the intrinsic anti-tumor activities of conventional immunoglobulin mAb formats, including the enhancement of effector cell functions and modulations of target binding properties, including interference with multiple signaling pathways. The second category of empowered biologics combines complementary anti-tumor modalities independent of the IgG format, including antibody drug conjugates (ADCs). In addition, bispecific compounds designed to recruit different subsets of inflammatory cells to the tumor environment, also belong to the mechanistic complementation strategy. This approach termed redirected immune cell killing, belongs to one the most promising new biotherapeutic platforms developed in oncology. Over 20 bispecific compounds are currently being developed pre-clinically, and several compounds are undergoing early stage clinical trials. In this report, we review the progress made in the development of bispecific biotherapeutics in the context of ADCs, redirected T- and B-cell killing and targeting of multiple signaling pathways. We also discuss the status of the clinical development of this class of compounds in oncology and the promises and challenges this field is currently facing.