Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity

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.

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

“…Mouse agonistic mAbs generated against human TRAIL-R1 and TRAIL-R2 also induce apoptosis in human tumour cells (Ichikawa et al, 2001;Ohtsuka et al, 2003;Yagita et al, 2004). In this report, we examine the activity of HGS-ETR1, a fully human TRAIL-R1 agonistic mAb, and our results confirm and extend these previous observations.…”

“…Agonistic TRAIL-R1 or TRAIL-R2 antibodies may have enhanced therapeutic potential due to a prolonged half-life in vivo compared to TRAIL ligand (Yagita et al, 2004). Proof of concept has been demonstrated with murine or rabbit monoclonal antibodies (mAbs) to human TRAIL-R1 or TRAIL-R2, which have antitumour activity in vitro and in vivo Muhlenbeck et al, 2000;Chuntharapai et al, 2001;Ichikawa et al, 2001). Mechanistically, these agonistic antibodies work by activation of TRAIL receptor-mediated apoptotic pathways in a manner similar to TRAIL, as a TRAIL-R1 antibody induced PARP cleavage in B-cell lymphoma 9D cells (Chuntharapai et al, 2001), and TRAIL-R2 antibodies induced activation of caspases and JNK/p38 kinase in tumour cells (Ichikawa et al, 2001;Ohtsuka et al, 2003).…”

“…Proof of concept has been demonstrated with murine or rabbit monoclonal antibodies (mAbs) to human TRAIL-R1 or TRAIL-R2, which have antitumour activity in vitro and in vivo Muhlenbeck et al, 2000;Chuntharapai et al, 2001;Ichikawa et al, 2001). Mechanistically, these agonistic antibodies work by activation of TRAIL receptor-mediated apoptotic pathways in a manner similar to TRAIL, as a TRAIL-R1 antibody induced PARP cleavage in B-cell lymphoma 9D cells (Chuntharapai et al, 2001), and TRAIL-R2 antibodies induced activation of caspases and JNK/p38 kinase in tumour cells (Ichikawa et al, 2001;Ohtsuka et al, 2003). Enhanced apoptotic signalling and cell killing in vitro has been observed with TRAIL-R1 and TRAIL-R2 antibodies in combination with chemotherapeutic agents (Ohtsuka et al, 2003).…”

Anticancer activity of oncolytic adenovirus vector armed with IFN-α and ADP is enhanced by pharmacologically controlled expression of TRAIL

“…[10][11][12][13][14][15] However, high concentrations of TRAIL were found to be toxic for normal human hepatocytes 16,17 and produced severe hepatitis in mice. 18 TRAIL-mediated hepatotoxicity can be controlled by pharmacologically regulated expression of TRAIL. 18 The TetON regulatable expression system allows for induction of gene expression by tetracycline or its analogue doxycycline (Dox); withdrawal of the inducer switches the expression off.…”

“…18 TRAIL-mediated hepatotoxicity can be controlled by pharmacologically regulated expression of TRAIL. 18 The TetON regulatable expression system allows for induction of gene expression by tetracycline or its analogue doxycycline (Dox); withdrawal of the inducer switches the expression off. 19 We constructed the RD Ad vector TetON-TRAIL, which expresses human TRAIL under the control of the TetON system.…”