Distinct function of monoclonal antibody to TRAIL-R2 as potentiator or inhibitor of the ligand TRAIL-induced apoptosis |
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Authors: | Mori Eiji Thomas Mayumi Motoki Kazuhiro Kataika Shiro |
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Affiliation: | Pharmaceutical Research Laboratories, Pharmaceutical Division, Kirin Brewery Co. Ltd., Takasaki, Gunma, Japan |
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Abstract: | 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. |
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Keywords: | TNF, tumor necrosis factor TRAIL, TNF-related apoptosis-inducing ligand sTRAIL, soluble TRAIL TRAIL-R, TRAIL receptor TRAIL-R2, TRAIL receptor 2 mAb, monoclonal antibody |
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