The NHance Mutation-Equipped Anti-MET Antibody ARGX-111 Displays Increased Tissue Penetration and Anti-Tumor Activity in Advanced Cancer Patients.

Fiche publication

Date publication

juin 2021

Journal

Biomedicines

Auteurs

Membres identifiés du Cancéropôle Est :
Dr BARTHELEMY Philippe , Pr BORG Christophe

Tous les auteurs :
Aftimos P, Rolfo C, Rottey S, Barthélémy P, Borg C, Park K, Oh DY, Kim SW, De Jonge N, Hanssens V, Zwanenpoel K, Molthoff C, Vugts D, Dreier T, Verheesen P, van Dongen GAMS, Jacobs J, Van Rompaey L, Hultberg A, Michieli P, Pauwels P, Fung S, Thibault A, de Haard H, Leupin N, Awada A

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/34200749

Résumé

Dysregulation of MET signaling has been implicated in tumorigenesis and metastasis. ARGX-111 combines complete blockade of this pathway with enhanced tumor cell killing and was investigated in 24 patients with MET-positive advanced cancers in a phase 1b study at four dose levels (0.3-10 mg/kg). ARGX-111 was well tolerated up to 3 mg/kg (MTD). Anti-tumor activity was observed in nearly half of the patients (46%) with a mean duration of treatment of 12 weeks. NHance mutations in the Fc of ARGX-111 increased affinity for the neonatal Fc receptor (FcRn) at acidic pH, stimulating transcytosis across FcRn-expressing cells and radiolabeled ARGX-111 accumulated in lymphoid tissues, bone and liver, organs expressing FcRn at high levels in a biodistribution study using human FcRn transgenic mice. In line with this, we observed, in a patient with MET-amplified (>10 copies) gastric cancer, diminished metabolic activity in multiple metastatic lesions in lymphoid and bone tissues by 18F-FDG-PET/CT after two infusions with 0.3 mg/kg ARGX-111. When escalated to 1 mg/kg, a partial response was reached. Furthermore, decreased numbers of CTC (75%) possibly by the enhanced tumor cell killing witnessed the modes of action of the drug, warranting further clinical investigation of ARGX-111.