Depleting MET-Expressing Tumor Cells by ADCC Provides a Therapeutic Advantage over Inhibiting HGF/MET Signaling

Hepatocyte growth factor (HGF) and its receptor Met represent validated targets for Cancer therapy. However, HGF/Met inhibitors being explored as Cancer therapeutics exhibit cytostatic activity rather than cytotoxic activity, which would be more desired. In this study, we engineered an antagonistic anti-MET antibody that, in addition to blocking HGF/Met signaling, also kills MET-overexpressing Cancer cells by antibody-dependent cellular cytotoxicity (ADCC). As a control reagent, we engineered the same antibody in an ADCC-inactive form that is similarly capable of blocking HGF/Met activity, but in the absence of any effector function. In comparing these two antibodies in multiple mouse models of Cancer, including HGF-dependent and -independent tumor xenografts, we determined that the ADCC-enhanced antibody was more efficacious than the ADCC-inactive antibody. In orthotopic mammary carcinoma models, ADCC enhancement was crucial to deplete circulating tumor cells and to suppress metastases. Prompted by these results, we optimized the ADCC-enhanced molecule for clinical development, generating an antibody (ARGX-111) with improved pharmacologic properties. ARGX-111 competed with HGF for Met binding, inhibiting ligand-dependent Met activity, downregulated cell surface expression of Met, curbing HGF-independent Met activity, and engaged natural killer cells to kill MET-expressing Cancer cells, displaying MET-specific cytotoxic activity. ADCC assays confirmed the cytotoxic effects of ARGX-111 in multiple human Cancer cell lines and patient-derived primary tumor specimens, including MET-expressing Cancer stem-like cells. Together, our results show how ADCC provides a therapeutic advantage over conventional HGF/Met signaling blockade and generates proof-of-concept for ARGX-111 clinical testing in MET-positive oncologic malignancies.