A New Anti-human Dr5 Monoclonal Antibody Tumor Killing Activity And Mechanism Of Action

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily with the ability to induce apoptosis in a wide variety of transformed cell lines of diverse origin. At least five receptors for TRAIL have been identified so far. Two of them, DR4 (TRAIL-R1) and DR5 (TRAIL-R2/TRICK2), are capable of transducing an apoptosis signal, whereas the other three, DcR1 (TRAIL-R3), DcR2 (TRAIL-R4) and osteoprotegerin (OPG), serve as decoy receptors to block TRAIL-mediated apoptosis. DR4 and DR5 share a common intracellular domain, called the death domain (DD), which is indispensable for initiation of the intracellular signaling cascade leading to cell death. TRAIL triggers multiple cell signals, including the activation of apoptotic caspase cascade, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) and NF-κB.In contrast to TNFs and Fas ligand (FasL), TRAIL has been known to induce apoptosis in a variety of tumor cells and some virally infected cells but not in most normal cells. The potential and safety of soluble TRAIL (sTRAIL) as an anticancer therapeutic agent has been demonstrated in mice and non-human primates. In addition to sTRAIL, monoclonal antibodies (mAbs) against TRAIL receptors with tumoricidal activity are also potential candidates for cancer therapy. There are a number of agonistic mAbs against human DR4 or DR5 reported in previous studies, most of which need crosslinkers to ensure effective killing of tumor cells. In 2001, Ichikawa et al. reported a mouse anti-DR5 mAb, TRA-8, which showed strong tumoricidal activity in the absence of cross-linking and had no hepatocyte toxicity. TRA-8 competes with TRAIL for binding to DR5 and almost entirely mimics the apoptosis-inducing mechanism of TRAIL. And the authors believed that DR5 was not sufficient to trigger apoptosis in normal hepatocytes. However, a recent study showed that at least some anti-DR5 and anti-DR4 mAbs did induce human hepatocytes apoptosis. So, we can not draw a definite conclusion on the hepatocyte toxicity of soluble TRAIL or mAbs against TRAIL receptors by now. Studies on the mechanism of anti-DR5 mAbs will help us to understand the complicated signal pathways mediated by DR5.