A Novel Anti-human DR5 Monoclonal Antibody with Tumoricidal Activity Induces Caspase-dependent and Caspase-independent Cell Death

Guo, Yabin; Chen, Caifeng; Zheng, Yong; Zhang, Jinchun; Tao, Xiaohui; Liu, Shilian; Zheng, Dexian; Liu, Yanxin

doi:10.1074/jbc.m503621200

Cited by 70 publications

(98 citation statements)

References 47 publications

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“…As reported by Guo et al [3], AD5-10 induces apoptosis of various tumor cell lines in the absence of cross-linking in vitro and exhibits a strong tumoricidal activity in vivo. AD5-10 does not induce cell death of human primary peripheral blood lymphocytes and normal hepatocytes, and injection with high doses of AD5-10 in mice causes no toxic reaction in liver, spleen, and kidney.…”

supporting

confidence: 52%

Antibody gene therapy: an attractive approach for the treatment of cancers and other chronic diseases

Zheng

2007

Cell Res

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supporting

confidence: 52%

Antibody gene therapy: an attractive approach for the treatment of cancers and other chronic diseases

Zheng

2007

Cell Res

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“…The cells were treated with a novel agonistic anti-human DR5 monoclonal antibody (AD5-10) that was developed in our lab [22], followed by a luciferase assay for NF-κB activation. As shown in Figure 6A, AD5-10 treatment significantly activated NF-κB in a dose-dependent manner.…”

Section: Dr5 Engagement By An Agonistic Antibody Activates Inflammatomentioning

confidence: 99%

TRAIL receptor mediates inflammatory cytokine release in an NF-κB-dependent manner

et al. 2009

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In the present article, we report that DR4 or DR5 overexpression dramatically activates the release of the inflammatory cytokines IL-8, TNF-α, CCL20, MIP-2 and MIP-1β in an NF-κB-dependent manner in 293T, MDA-MB-231 and HCT-116 cells. We showed that death receptor-mediated signals were extracellular domain-independent, whereas the effect of overexpression of the DR4 intracellular domain was much less potent. The TRADD-TRAF2-NIK-IKKα/β signaling cascade, which plays an essential role in TNF-induced NF-κB activation, was found to be involved in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated signal transduction. The FADD-caspase signaling pathway, which has been reported to be mostly related to apoptosis, was identified as being essential for DR4 or DR5 overexpression-mediated NF-κB activation and cytokine secretion and crosstalks with the TRADD-TRAF2-NIK-IKKα/β signaling cascade. Furthermore, a DR5 agonistic antibody (AD5-10) triggered the inflammatory cytokine release. These data, together with previous reports, provide strong evidence that TRAIL and TRAIL receptors play an important role in inflammation.

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“…In addition to the cognate ligand of recombinant TRAIL, several agonistic monoclonal antibodies (mAb) have been developed by targeting DR4 (7)(8)(9)(10) or DR5 (11)(12)(13)(14)(15)(16), which also induce cell death in various types of tumors in vitro and in vivo. Some of them are now under various phases of clinical trials (1)(2)(3)10).…”

Section: Introductionmentioning

confidence: 99%

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

Sung

Park²,

Lee³

et al. 2009

Molecular Cancer Therapeutics

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The proapoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors death receptor (DR) 4 and DR5 are attractive targets to develop the receptorspecific agonistic monoclonal antibodies (mAb) as anticancer agents because of their tumor-selective cell death-inducing activity. Here, we report a novel agonistic mAb, AY4, raised against human DR4 in mice. ELISA analysis revealed that AY4 specifically bound to DR4 without competition with TRAIL for the binding. Despite distinct binding regions of AY4 on DR4 from those of TRAIL, AY4 as a single agent induced caspase-dependent apoptotic cell death of several tumor types through the extrinsic and/or intrinsic pathways without substantial cytotoxicity to normal human hepatocytes. Further, the AY4-sensitive cells followed the same cell death characteristics classified as type I and type II cells by the response to TRAIL, suggesting that the cell death profiles in responses to DR4 and/or DR5 stimulation are determined by the downstream signaling of the receptor rather than the kind of receptor. Noticeably, AY4 efficiently induced cell death of Jurkat cells, which have been reported to be resistant to other anti-DR4 agonistic mAbs, most likely due to the unique epitope property of AY4. In vivo administration of AY4 significantly inhibited tumor growth of human non-small cell lung carcinoma preestablished in athymic nude mice. Conclusively, our results provide further insight into the DR4-mediated cell death signaling and potential use of AY4 mAb as an anticancer therapeutic agent, particularly for

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A Novel Anti-human DR5 Monoclonal Antibody with Tumoricidal Activity Induces Caspase-dependent and Caspase-independent Cell Death

Cited by 70 publications

References 47 publications

Antibody gene therapy: an attractive approach for the treatment of cancers and other chronic diseases

Antibody gene therapy: an attractive approach for the treatment of cancers and other chronic diseases

TRAIL receptor mediates inflammatory cytokine release in an NF-κB-dependent manner

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

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