The nhance® mutation-equipped anti-met antibody argx-111 displays increased tissue penetration and anti-tumor activity in advanced cancer patients

Philippe Aftimos, Christian Rolfo, Sylvie Rottey, Philippe Barthélémy, Christophe Borg, Keunchil Park, Do-Youn Oh, Sang-We Kim, Natalie de Jonge, Valérie Hanssens, Karen Zwanenpoel, Carla Molthoff, Daniëlle Vugts, Torsten Dreier, Peter Verheesen, Guus A. M. S. van Dongen, Julie Jacobs, Luc van Rompaey, Anna Hultberg, Paolo MichieliPatrick Pauwels, Samson Fung, Alain Thibault, Hans de Haard, Nicolas Leupin*, Ahmad Awada

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article number665
JournalBiomedicines
Volume9
Issue number6
DOIs
Publication statusPublished - 1 Jun 2021

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