Fiche publication
Date publication
mars 2015
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BORG Christophe
Tous les auteurs :
Hanssens V, De Jonge N, Hultberg A, Borg C, Michieli P, Dreier T, de Haard H, Thibault A
Lien Pubmed
Résumé
BACKGROUND: Signalling through MET, the hepatocyte growth factor (HGF) receptor, plays a key role in tumor progression and metastasis. In cancer patients, molecules antagonizing HGF/MET interaction induce incomplete blockade of MET and are primarily associated with cytostatic activity. To overcome this limitation, we developed ARGX-111, an afucosylated anti-MET antibody that blocks both HGF dependent and independent signalling and kills circulating MET-expressing cancer cells through enhanced ADCC. MATERIALS AND METHODS: ARGX-111 was developed using the SIMPLE Antibody platform and was mutated in its Fc region for increased tissue penetration and afucosylated for enhanced ADCC. An ADCC-dead version of ARGX-111 was made to specifically evaluate the contribution of ADCC to ARGX-111 mechanisms of action. Bioassays using cell lines and primary patient-derived leukemia cells were used to evaluate the ADCC properties of the molecule. Orthotopic mouse models of metastatic breast cancer using MDA-MB-231 cells were applied to evaluate the effect of ARGX-111 on circulating tumor cells (CTCs) and metastasis. RESULTS: In ADCC assays using NK cells from healthy donors, ARGX-111 killed a variety of MET-expressing human cancer cells (including human tumor cell lines with low MET density) and patient-derived CLL and AML cells; ARGX-111 induced 40% to 60% cell lysis in low MET expressing cells and 60% lysis in high Met expressing cells. In orthotopic mouse models of metastatic breast carcinoma, ARGX-111 reduced CTC numbers and metastasis formation. For example mice treated with ARGX-111 displayed 89% less CTCs compared to the isotype control and 81% less CTCs compared to the ADCC-dead version of ARGX-111. CONCLUSIONS: These data indicate that combining inhibition of HGF/MET signalling with promotion of ADCC results in increased anti-tumor activity, generating proof-of-concept for clinical testing of ARGX-111 in MET-positive oncological malignancies including leukemias. ARGX-111 is currently undergoing phase I testing in patients with hematological malignancies and solid tumors associated with CTCs.
Référence
Ann Oncol. 2015 Mar;26 Suppl 2:ii31
