Dual-functional super bispecific nano-antibodies derived from monoclonal antibodies potentiate the antitumor effect of innate immune cells

Innate immune cells, including natural killer cells and macrophages, are crucial in tumor surveillance and elimination. In contrast to the relatively complicated process of antigen-specific adaptive immunity, innate immune cells exhibit spontaneous tumoricidal effects by releasing cytolytic granules to adjacent tumor cells or by directly phagocytizing adjacent tumor cells. These effects of innate immune cells highlight the importance and necessity of spatial proximity between activated effector cells and tumor cells in innate antitumor immunity. Here, we describe two dual-functional super bispecific nano-antibodies (S-BsNA) constructed by immobilizing two types of traditional monoclonal antibodies (αKLRG1 and αPDL1, or αCSF1R and αCD47) onto a universal antibody-immobilization platform. The S-BsNA simultaneously regulate the antitumor response of innate immune cells and establish a close physical connection between effector cells and tumor cells. The superiority of S-BsNA over the parental monoclonal antibodies was evaluated in multiple tumor models in vitro and in vivo. S-BsNA can efficiently augment innate antitumor immunity both in vitro and in vivo and can be an alternative modality of immunotherapy, expanding its benefits to a larger patient pool.