MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM

Significance AlthoughMET is an established oncogene that drives tumorigenesis, metastasis, and resistance to therapy, antibody therapeutics targeting Met have thus far eluded successful clinical development. Met is a particularly challenging target because bivalent antibodies typically agonize Met, whereas monovalent antibodies lack potency and the capacity to downregulate it. We report the design and preclinical development of a purely antagonistic anti-Met antibody that potently blocks both ligand-dependent and ligand-independent signaling by exploiting the concept of avidity. MM-131 is a bispecific antibody that is monovalent for Met, but exhibits high avidity by concurrently binding to the tumor-specific antigen epithelial cell adhesion molecule. Preclinically, MM-131 inhibits proliferation in Met-driven cancer cells, inhibits hepatocyte growth factor (HGF)-mediated cell migration, and inhibits tumor growth in HGF-dependent and -independent mouse xenograft models.