TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces apoptosis upon binding to its functional receptors DR4 and DR5 on the surface of tumor cells. We have generated an anti-DR5 agonistic antibody by hybridoma technology and functional cell based screening. LBY135 specifically binds to DR5 with single digit nM affinity, mimics TRAIL to induce cell death in tumor cells, and has little effect on most normal cells in vitro. LBY135 appears to mediate cell death mainly through apoptosis, as demonstrated by the activation of caspase 3, with moderate ADCC and no CDC activity in in vitro assays. This is further supported by the relative in vivo efficacy of various chimeric forms of the antibody (murine IgG1, human IgG1, and IgG4 Fc) and by the robust activation of Caspases in vivo. LBY135 provides a means to interrogate the mechanisms of TRAIL induced tumor specific cell death. It also demonstrates promise as a novel therapeutic for cancer treatment.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA