Depleting MET-expressing tumor cells by ADCC provides a therapeutic advantage over inhibiting HGF/MET signaling

Anna Hultberg, Virginia Morello, Leander Huyghe, Natalie De Jonge, Christophe Blanchetot, Valérie Hanssens, Gitte De Boeck, Karen Silence, Els Festjens, Raimond Heukers, Benjamin Roux, Fabienne Lamballe, Christophe Ginestier, Emmanuelle Charafe-Jauffret, Flavio Maina, Peter Brouckaert, Michael Saunders, Alain Thibault, Torsten Dreier, Hans De HaardPaolo Michieli

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3373-3383
Number of pages11
JournalCancer Research
Volume75
Issue number16
DOIs
Publication statusPublished - Aug 15 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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