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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-1/2 (TRAIL-R1/R2), also known as death receptors, are expressed in a wide variety of tumor cells. Although TRAIL can induce cell apoptosis by engaging its cognate TRAIL-R1/R2, some tumor cells are or become resistant to TRAIL treatment. Monoclonal antibodies (mAbs) against TRAIL-R1/R2 have been developed to use as potential antitumor therapeutic agents instead of TRAIL. However, TRAIL-R1/R2-based tumor therapy has not yet been realized. We previously generated a series of fully human monoclonal antibodies against TRAIL-R1 (TR1-mAbs) that induced tumor cell apoptosis. In this study, we identified the antigenic binding sites of these TR1-mAbs and proposed two major epitopes on the extracellular domain of TRAIL-R1. The analysis revealed that the epitopes of some TR1-mAbs partially overlaps with the beginning of TRAIL-binding sites, and other epitopes are located within the TRAIL-binding region. Among these mAbs, TR1-422 and TR1-419 mAbs have two antigenic binding sites that bound to the same binding region, but they have different essential amino acid residues and binding site sizes. Furthermore, we investigated the apoptosis activity of TR1-419 and TR1-422 mAbs in the form of IgG and IgM. In contrast to the IgG-type TR1-419 and TR1-422 mAbs, which enhanced and inhibited TRAIL-induced apoptosis, respectively, both IgM-type TR1-419 and TR1-422 mAb strongly induced cell apoptosis with or without soluble TRAIL (sTRAIL). Moreover, the results showed that IgM-type TR1-419 and TR1-422 mAbs alone can sufficiently activate the extrinsic and intrinsic apoptosis signaling pathways and suppress tumor growth in vivo . Consequently, we identified two antigenic binding sites with agonistic activity, and their specific IgM-type mAbs exhibited strong cytotoxic activity in tumor cells in vitro and in vivo . Thus, these agonistic antigenic binding sites may be useful for the development of effective Ab-based drugs or Ab-based cell immunotherapy for various human solid tumors.

Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1