Abstract
Agonistic tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-receptor-specific antibodies are attractive antitumor therapeutics. Recently, our group has generated several human monoclonal antibodies (mAbs) to TRAIL-receptor-1 (TRAIL-R1) (TR1-IgGs) using ISAAC technology. However, these TR1-IgGs did not demonstrate ideal apoptosis-inducing capacity in the absence of additional antibodies. To overcome this limitation, we class-switched the TR1-IgGs to TRAIL-R1 IgM antibodies (TR1-IgMs); TR1-IgMs might possess high valency and facilitate the crosslinking of the cell surface receptors. We showed that the TR1-IgMs bound TRAIL-R1, activated the caspase signal, and induced strong apoptosis (100-fold higher compared with the IgG form in one case) in human tumor cell lines without any additional crosslinking in vitro. We further demonstrated that these TR1-IgMs dramatically inhibited tumor growth in a xenograft model through the caspase activation cascade. These data suggest that TR1-IgMs may become potential immunotherapeutic agents for cancer therapy.