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 pharmacological properties. ARGX-111 competed with HGF for MET binding, inhibiting ligand-dependent MET activity; down-regulated cell surface expression of MET, curbing HGF-independent MET activity; and engaged NK 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 generate proof-of-concept for ARGX-111 clinical testing in MET-positive oncological malignancies.

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

Morello, Virginia;Michieli, Paolo
Last
2015

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 pharmacological properties. ARGX-111 competed with HGF for MET binding, inhibiting ligand-dependent MET activity; down-regulated cell surface expression of MET, curbing HGF-independent MET activity; and engaged NK 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 generate proof-of-concept for ARGX-111 clinical testing in MET-positive oncological malignancies.
75
16
3373
3383
http://cancerres.aacrjournals.org/content/75/16/3373.full.pdf+html
Animals; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Binding, Competitive; Breast Neoplasms; Cell Line, Tumor; Female; Flow Cytometry; Hepatocyte Growth Factor; Humans; Mice, Nude; Neoplasms; Protein Binding; Proto-Oncogene Proteins c-met; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays; Oncology; Cancer Research
Hultberg, Anna; Morello, Virginia; Huyghe, Leander; De Jonge, Natalie*; Blanchetot, Christophe; Hanssens, Valérie; De Boeck, Gitte; Silence, Karen; Festjens, Els; Heukers, Raimond; Roux, Benjamin; Lamballe, Fabienne; Ginestier, Christophe; Charafe-Jauffret, Emmanuelle; Maina, Flavio; Brouckaert, Peter; Saunders, Michael; Thibault, Alain; Dreier, Torsten; De Haard, Hans; Michieli, Paolo
File in questo prodotto:
File Dimensione Formato  
37_Hultberg et al_Cancer Res 2015.pdf

Accesso riservato

Descrizione: Articolo principale
Tipo di file: PDF EDITORIALE
Dimensione 933.51 kB
Formato Adobe PDF
933.51 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
145021_1_merged_1431331522.pdf

Accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 1.24 MB
Formato Adobe PDF
1.24 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1671375
Citazioni
  • ???jsp.display-item.citation.pmc??? 18
  • Scopus 28
  • ???jsp.display-item.citation.isi??? 30
social impact