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• W2783442801 abstract "e14016 Background: ARGX-111 is a therapeutic antibody candidate combining three independent MoA: i. blockade of HGF-dependent and -independent MET activity, ii. enhanced ADCC and iii. increased tissue penetration through enhanced FcRn binding. A Phase-I study (NCT02055066) in patients with c-MET-amplified tumors is ongoing. A new hypothesis for depletion of MET-positive MDSCs in the tumor microenvironment is also investigated. Methods: c-MET amplification detected using FISH on tumor biopsies is a prescreening requisite for patient selection in the expansion phase. MDSCs were enumerated by FACS using blood and ascites from patients or tumor and spleen tissue from a mouse CT26 syngeneic tumor model. Results: ARGX-111 dose escalation indicated a favorable safety profile and fixed a 3 mg/kg bi-weekly dose for the safety expansion in c-MET-amplified patients. Efficacy signals were seen in the c-MET-amplified setting [J Clin Oncol 33, 2015 (suppl; abstr 2580)]. FISH screening identified 4% of c-MET-amplified biopsies (5/124; MET/CEP7 ratio: 2.5-14.1): gastric: 2/13; gall bladder: 1/8, RCC: 2/9. Treatment of the patients is ongoing and clinical results from the expansion cohort will be presented at the meeting. MET-positive MDSCs were isolated from healthy subjects, cancer patients (RFI > 2 for 4/8 patients vs. 3/8 controls) and from ascites of pancreatic cancer patients (2/2). Ex vivo depletion by ARGX-111 was observed based on its enhanced ADCC. In the CT26 syngeneic tumor model, the spleen of tumor-bearing mice displayed an increased MDSC/CD8+ cytotoxic T-cell ratio compared to control mice without tumor. MET expression was confined to monocytic MDSCs (10-25%) in the spleen while in tumor tissue, both granulocytic and monocytic MDSCs expressed MET ( > 90%). Conclusions: ARGX-111 displays a promising safety and biological activity profile in c-MET amplified patients in the ongoing Phase-I trial. Preclinical studies demonstrated depletion of MET-positive MDSCs by ARGX-111, providing an exciting new perspective for therapeutic intervention in MET cancer biology by targeting of both the tumor cells and the tumor microenvironment. Clinical trial information: NCT0205506." @default.
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• W2783442801 date "2016-05-20" @default.
• W2783442801 modified "2023-10-18" @default.
• W2783442801 title "ARGX-111 shows activity in MET-amplified patients in a phase-I study and in preclinical models of myeloid-derived suppressor cell (MDSC) depletion in the tumor microenvironment." @default.
• W2783442801 doi "https://doi.org/10.1200/jco.2016.34.15_suppl.e14016" @default.
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