|
Title
|
|
|
|
The NHance mutation-equipped anti-MET antibody ARGX-111 displays increased tissue penetration and anti-tumor activity in advanced cancer patients
| |
|
Author
|
|
|
|
| |
|
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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Biomedicines / Multidisciplinary Digital Publishing Institute. - 2013, currens
| |
|
Publication
|
|
|
|
2021
| |
|
ISSN
|
|
|
|
2227-9059
| |
|
DOI
|
|
|
|
10.3390/BIOMEDICINES9060665
| |
|
Volume/pages
|
|
|
|
9
:6
(2021)
, 19 p.
| |
|
Article Reference
|
|
|
|
665
| |
|
ISI
|
|
|
|
000665593700001
| |
|
Pubmed ID
|
|
|
|
34200749
| |
|
Medium
|
|
|
|
E-only publicatie
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|