Predominant antitumor effects by fully human anti-TRAIL-receptor 2 (DR5) monoclonal antibodies in human glioma cells in vitro and in vivo.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2 L) preferentially induces apoptosis in human tumor cells through its cognate death receptors DR4 or DR5, thereby being investigated as a potential agent for cancer therapy. Here, we applied fully human anti-human TRAIL receptor monoclonal antibodies (mAbs) to specifically target one of death receptors for TRAIL in human glioma cells, which could also reduce potential TRAIL-induced toxicity in humans. Twelve human glioma cell lines treated with several fully human anti-human TRAIL receptor mAbs were sensitive to only anti-DR5 mAbs, whereas they were totally insensitive to anti-DR4 mAb. Treatment with anti-DR5 mAbs exerted rapid cytotoxicity and lead to apoptosis induction. The cellular sensitivity was closely associated with cell-surface expression of DR5. Expression of c-FLIP(L), Akt, and Cyclin D1 significantly correlated with sensitivity to anti-DR5 mAbs. Primary cultures of glioma cells were also relatively resistant to anti-DR5 mAbs, exhibiting both lower DR5 and higher c-FLIP(L) expression. Downregulation of c-FLIP(L) expression resulted in the sensitization of human glioma cells to anti-DR5 mAbs, whereas overexpression of c-FLIP(L) conferred resistance to anti-DR5 mAb. Treatment of tumor-burden nude mice with the direct agonist anti-DR5 mAb KMTR2 significantly suppressed growth of subcutaneous glioma xenografts leading to complete regression. Similarly, treatment of nude mice bearing intracerebral glioma xenografts with KMTR2 significantly elongated lifespan without tumor recurrence. These results suggest that DR5 is the predominant TRAIL receptor mediating apoptotic signals in human glioma cells, and sensitivity to anti-DR5 mAbs was determined at least in part by the expression level of c-FLIP(L) and Akt. Specific targeting of death receptor pathway through DR5 using fully human mAbs might provide a novel therapeutic strategy for intractable malignant gliomas.
Department of Neurosurgery, Kyorin University Faculty of Medicine, Mitaka, Tokyo 181-8611, Japan. nagane-nsu@umin.ac.jp
Motoo
M
Nagane
Saki
S
Shimizu
Eiji
E
Mori
Shiro
S
Kataoka
Yoshiaki
Y
Shiokawa
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors* / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand