title: Depleting MET-Expressing Tumor Cells by ADCC Provides a Therapeutic Advantage over Inhibiting HGF/MET Signaling.
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.
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium. paolo.michieli@ircc.it ahultberg@argen-x.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Hultberg
authors.affiliation: Department of Oncology, University of Torino Medical School, Candiolo, Turin, Italy. Laboratory of Experimental Therapy, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Morello
authors.affiliation: Department of Molecular Biomedical Research, Inflammation Research Center, Ghent University, Zwijnaarde, Belgium.
authors.forename: Leander
authors.initials: L
authors.lastname: Huyghe
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium.
authors.forename: Natalie
authors.initials: N
authors.lastname: De Jonge
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanchetot
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hanssens
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium.
authors.forename: Gitte
authors.initials: G
authors.lastname: De Boeck
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Silence
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Festjens
authors.affiliation: Department of Biology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Raimond
authors.initials: R
authors.lastname: Heukers
authors.affiliation: Aix-Marseille Université, IBDM, CNRS UMR 7288, Parc Scientifique de Luminy, Marseille, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Roux
authors.affiliation: Aix-Marseille Université, IBDM, CNRS UMR 7288, Parc Scientifique de Luminy, Marseille, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lamballe
authors.affiliation: Aix-Marseille Université, CRCM, Institut Paoli-Calmettes, CNRS UMR 7258, Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Ginestier
authors.affiliation: Aix-Marseille Université, CRCM, Institut Paoli-Calmettes, CNRS UMR 7258, Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charafe-Jauffret
authors.affiliation: Aix-Marseille Université, IBDM, CNRS UMR 7288, Parc Scientifique de Luminy, Marseille, France.
authors.forename: Flavio
authors.initials: F
authors.lastname: Maina
authors.affiliation: Department of Molecular Biomedical Research, Inflammation Research Center, Ghent University, Zwijnaarde, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium.
authors.forename: Michael
authors.initials: M
authors.lastname: Saunders
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Thibault
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium.
authors.forename: Torsten
authors.initials: T
authors.lastname: Dreier
authors.affiliation: arGEN-X BVBA, Zwijnaarde, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: de Haard
authors.affiliation: Department of Oncology, University of Torino Medical School, Candiolo, Turin, Italy. Laboratory of Experimental Therapy, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy. paolo.michieli@ircc.it ahultberg@argen-x.com.
authors.forename: Paolo
authors.initials: P
authors.lastname: Michieli
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C000602819:ARGX-111; D000911:Antibodies, Monoclonal; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met