Aftimos Philippe, Rolfo Christian, Rottey Sylvie, Barthélémy Philippe, Borg Christophe, Park Keunchil, Oh Do-Youn, Kim Sang-We, De Jonge Natalie, Hanssens Valérie, Zwanenpoel Karen, Molthoff Carla, Vugts Daniëlle, Dreier Torsten, Verheesen Peter, van Dongen Guus A M S, Jacobs Julie, Van Rompaey Luc, Hultberg Anna, Michieli Paolo, Pauwels Patrick, Fung Samson, Thibault Alain, de Haard Hans, Leupin Nicolas, Awada Ahmad
Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium.
University Hospital Antwerp, 2650 Edegem, Belgium.
Biomedicines. 2021 Jun 10;9(6):665. doi: 10.3390/biomedicines9060665.
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.
MET信号通路失调与肿瘤发生和转移有关。ARGX-111在阻断该信号通路的同时增强肿瘤细胞杀伤作用，并在一项1b期研究中对24例MET阳性晚期癌症患者进行了四个剂量水平（0.3-10mg/kg）的研究。ARGX-111在高达3mg/kg（最大耐受剂量）时耐受性良好。近一半（46%）的患者观察到抗肿瘤活性，平均治疗持续时间为12周。ARGX-111的Fc段中的NHance突变在酸性pH下增加了对新生儿Fc受体（FcRn）的亲和力，刺激其跨表达FcRn的细胞进行转胞吞作用，并且在一项使用人FcRn转基因小鼠的生物分布研究中，放射性标记的ARGX-111在淋巴组织、骨骼和肝脏（高水平表达FcRn的器官）中蓄积。与此一致的是，在一名MET扩增（>10拷贝）的胃癌患者中，在两次输注0.3mg/kg ARGX-111后，18F-FDG-PET/CT显示淋巴和骨组织中的多个转移病灶代谢活性降低。当剂量增至1mg/kg时，达到了部分缓解。此外，循环肿瘤细胞数量减少（75%），可能是由于增强的肿瘤细胞杀伤作用，这证明了该药物的作用方式，值得对ARGX-111进行进一步的临床研究。
