Distinct function of monoclonal antibody to TRAIL-R2 as potentiator or inhibitor of the ligand TRAIL-induced apoptosis.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) specifically induces apoptosis in tumor cells but may be toxic to human hepatocytes. Although hepatocytes are susceptible to apoptotic signals mediated by TRAIL-receptor 2 (TRAIL-R2), we previously reported that some anti-TRAIL-R2 monoclonal antibodies (mAbs) produce little hepatocyte toxicity. Those mAbs neutralized the cytotoxic activity of TRAIL by inhibiting receptor-ligand binding. The hepatocyte-toxic mAbs did not compete with TRAIL for binding to TRAIL-R2, and potentiated ligand activity in both cancer cells and hepatocytes. A neutralizing antibody to TRAIL inhibited hepatocyte death by anti-TRAIL-R2 mAbs, suggesting that the toxicity may reflect their ability to potentiate membrane-bound TRAIL on hepatocytes.
Mori
Eiji
E
Pharmaceutical Research Laboratories, Pharmaceutical Division, Kirin Brewery Co. Ltd., Takasaki, Gunma, Japan
Thomas
Mayumi
M
Motoki
Kazuhiro
K
Kataika
Shiro
S
D000911:Antibodies, Monoclonal / Q000276:immunology*; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha