A novel humanized anti‐tumor necrosis factor‐related apoptosis‐inducing ligand‐R2 monoclonal antibody induces apoptotic and autophagic cell death

Abstract

It is well known that the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10) is specifically expressed in various tumor cells, but less or no expression in most normal tissues and cells. While TRAIL engages with its native death receptors, TRAIL receptor 1 (TRAIL-R1) or 2 (TRAIL-R2), usually elicits the tumor cell death by apoptosis. In this study, we report that a novel humanized monoclonal antibody against TRAIL-R2 (named as zaptuzumab) well remain the biological activity of the parental mouse antibody AD5-10 inducing cell death in various cancer cells, but little effect on normal cells. Zaptuzumab also markedly inhibited the tumor growth in the mouse xenograft of NCI-H460 without toxicity to the liver and kidney, and the efficacy of tumor suppression was increased significantly while it combined with cis-dichlorodiamineplatinum. Especially, I-labeled zaptuzumab injected into mouse tail vein specifically targeted to the xenograft of the lung cancer cells. Confocal analysis showed that zaptuzumab bound with TRAIL-R2 on cell surface could be quickly internalized and transferred into the lysosome. Furthermore, zaptuzumab possessed a high level of antibody-dependent cytotoxicity as well as complement-dependent cytotoxicity. Study on the mechanisms of cell death induced by zaptuzumab showed that it efficiently induced both caspase-dependent apoptosis and autophagic cell death. These data suggest that the humanized anti-TRAIL-R2 monoclonal antibody or the second generation of the antibody may have an important clinical usage for cancer immunotherapy. © 2017 IUBMB Life, 69(9):735-744, 2017.

Anticancer Activity and Mechanism of Xanthohumol: A Prenylated Flavonoid From Hops (Humulus lupulus L.)

“…TRAIL, an endogenous ligand, plays a crucial role in anti-tumor immunity and immune surveillance ( Chen et al, 2017 ), while LNCaP PCa cells are resistant to TRAIL-induced apoptosis. It should be noted that Xn increased sensitivity of LNCaP to TRAIL, which maybe another important mechanism of Xn-induced PCa cells apoptosis ( Klosek et al, 2016 ).…”

Involvement of p38 Activation and Mitochondria in Death of Human Leukemia Cells Induced by an Agonistic Human Monoclonal Antibody Fab Specific to TRAIL Receptor 1

“…Agonistic TRAIL receptor mAbs or Fab fragments such as DR4-4 Fab and other mAbs [5,6,8,9,12] may provide more efficient immunotherapy for cancer than TRAIL. Many DR agonists have been demonstrated to be safe and promising for cancer immunotherapy in phase I, II, and III clinical trials [28,31,32].…”

“…Different mAbs to DR4 and DR5 can exert their cytotoxic activities via various mechanisms. Some mAbs against DRs induce a caspase-dependent mechanism mimicking that of sTRAIL [29,30,31]. However, a mouse anti-DR5 mAb, AD5-10, induced both caspase-dependent and -independent cell death in Jurkat cells [23].…”

“…However, a mouse anti-DR5 mAb, AD5-10, induced both caspase-dependent and -independent cell death in Jurkat cells [23]. Zaptuzumab, a humanized version of AD5-10, induced caspase-dependent apoptosis and autophagic cell death [31]. Human agonistic mAbs HGS-ETR1 (anti-DR4) and HGS-ETR2 (anti-DR5) killed myeloma and lymphoma cells through caspase activation and cleavage of myeloid cell leukemia-1L [29].…”

“…A human mAb against DR5, lexatumumab, showed some clinical effectiveness for pediatric solid tumors, where, in combination with radiation therapy, it enhanced antitumor activity [32]. Many human and humanized agonists of DR4 and DR5 including the abovementioned antibodies (Abs) are currently being studied in preclinical or clinical trials for various cancers [28,31,32,33].…”