Lu, Y.; Qiu, S.; Fan, Z.

We conceived of a new anti-tumor mechanism of action by which a soluble target in tumor microenvironment, such as a tumor-driving growth factor, can be phagocytized along with cancer cells via antibody-dependent cellular phagocytosis (ADCP) using an antibody bispecific for the soluble target and a solid target overexpressed on cancer cell surface. In this study, we explored the conception through engineering a pair of bispecific antibodies (BsAbs) co-targeting human epidermal growth factor receptor-2 (HER2) and human or mouse vascular endothelial growth factor A (VEGFA). We showed that the HER2-VEGFA BsAbs but not the parental antibodies alone or in combination induced co-phagocytosis of VEGFA and HER2-overexpressing cancer cells by tumor-associated macrophages via ADCP. In both immunocompromised and immunocompetent mice with aggressive tumors, the BsAbs demonstrated a greater anti-metastasis activity and had a greater survival benefit than the parental antibodies, alone or in combination, in a manner dependent on Fc{gamma} receptors on the macrophages. Our results provide the proof-of-concept to induce VEGFA co-phagocytosis using HER2-VEGFA BsAbs to achieve enhanced antitumor activities by leveraging overexpressed HER2 on cancer cell surface. Our findings warrant clinical testing of the humanized BsAb to treat metastasis and recurrence of HER2-overexpressing solid tumors that respond to anti-VEGFA therapy.