Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Cancer Res. 2015 Aug 15;75(16):3373-83. doi: 10.1158/0008-5472.CAN-15-0356. Epub 2015 Jul 3.

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

Author information

1
arGEN-X BVBA, Zwijnaarde, Belgium. paolo.michieli@ircc.it ahultberg@argen-x.com.
2
Department of Oncology, University of Torino Medical School, Candiolo, Turin, Italy. Laboratory of Experimental Therapy, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy.
3
Department of Molecular Biomedical Research, Inflammation Research Center, Ghent University, Zwijnaarde, Belgium.
4
arGEN-X BVBA, Zwijnaarde, Belgium.
5
Department of Biology, Utrecht University, Utrecht, the Netherlands.
6
Aix-Marseille Université, IBDM, CNRS UMR 7288, Parc Scientifique de Luminy, Marseille, France.
7
Aix-Marseille Université, CRCM, Institut Paoli-Calmettes, CNRS UMR 7258, Marseille, France.
8
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.

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.

PMID:
26141862
DOI:
10.1158/0008-5472.CAN-15-0356
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center