Related Experiment Video
Updated: Jul 8, 2026
A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity
1Biomedical Research Laboratories, Sankyo Co., Tokyo, Japan.
Abstract:
A novel anti-human DR5 monoclonal antibody, TRA-8, induces apoptosis of most tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-sensitive tumor cells both in vitro and in vivo. In contrast to both the membrane-bound form of human TRAIL, which induced severe hepatitis in mice, and the soluble form of human TRAIL, which induced apoptosis of normal human hepatocytes in vitro, TRA-8 did not induce significant cell death of normal human hepatocytes. However, both primary hepatocellular carcinoma cells and an established liver cancer cell line were highly susceptible to the killing mediated by TRA-8. We show here that elevated levels of cell-surface expression of DR5 and increased susceptibility to DR5-mediated apoptosis are characteristics of malignant tumor cells. In contrast, DR5 alone is not sufficient to trigger apoptosis of normal hepatocytes. Therefore, selective, specific targeting of DR5 with an agonistic antibody might be a safe and effective strategy for cancer therapy.
Insights
A novel antibody, TRA-8, targets DR5 to induce cancer cell death while sparing normal liver cells. This selective targeting of DR5 offers a promising strategy for safe and effective cancer therapy.
Area of Science:
- Immunology
- Oncology
- Hepatology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor DR5 are involved in apoptosis.
- TRAIL therapy has shown potential but faces challenges due to toxicity in normal cells, particularly hepatocytes.
- DR5 expression is elevated on many cancer cells, suggesting it as a potential therapeutic target.
Purpose of the Study:
- To evaluate the efficacy and safety of a novel anti-human DR5 monoclonal antibody, TRA-8, in cancer treatment.
- To investigate the role of DR5 expression in cancer cell susceptibility to apoptosis.
- To compare the effects of TRA-8 with TRAIL on normal hepatocytes and tumor cells.
Main Methods:
- In vitro and in vivo studies using the anti-DR5 antibody TRA-8.
- Assessment of apoptosis induction in various cancer cell lines and normal human hepatocytes.
- Comparison of TRA-8's effects with membrane-bound and soluble forms of human TRAIL.
- Analysis of DR5 cell-surface expression levels on tumor cells and normal hepatocytes.
Main Results:
- TRA-8 effectively induced apoptosis in most TRAIL-sensitive tumor cells both in vitro and in vivo.
- TRA-8 did not cause significant cell death in normal human hepatocytes, unlike TRAIL.
- Primary hepatocellular carcinoma cells and a liver cancer cell line were highly susceptible to TRA-8-mediated killing.
- Elevated DR5 expression correlated with increased susceptibility to DR5-mediated apoptosis in malignant tumor cells.
Conclusions:
- Selective targeting of DR5 with agonistic antibodies like TRA-8 is a potentially safe and effective cancer therapy strategy.
- Malignant tumor cells exhibit increased DR5 expression and susceptibility to DR5-mediated apoptosis, while normal hepatocytes are relatively resistant.
- TRA-8 demonstrates a favorable therapeutic window, sparing normal liver cells while eliminating cancer cells.
