Apo2L/TRAIL and the Death Receptor 5 Agonist Antibody AMG 655 Cooperate to Promote Receptor Clustering and Antitumor Activity

Graves, Jonathan D.; Kordich, Jennifer J.; Huang, Tzu-Hsuan; Piasecki, Julia; Bush, Tammy L.; Sullivan, Timothy J.; Foltz, Ian N.; Chang, Wesley; Douangpanya, Heather; Dang, Thu Thi; O’Neill, Jason; Mallari, Rommel; Zhao, Xiaoning; Branstetter, Daniel; Rossi, John M.; Long, Alexander; Huang, Xin; Holland, Pamela M.

doi:10.1016/j.ccr.2014.04.028

Cited by 142 publications

(156 citation statements)

References 53 publications

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“…3A) (70), in the intracellular FasDD-FADD complex (Fig. 3B) (73), and for TRAF2 and TRAF6 oligomerization, consistent with a hexagonal lattice geometry (Fig.…”

Section: Tnfrsf Signaling May Be Described By a Uniform Hexagonal Modsupporting

confidence: 63%

“…However, more recent studies have found that the combination of DR5-specific antibodies and hrTRAIL can synergize to kill cancer cells both in vitro (70,71) and in vivo (70). This combination therapy proved beneficial even in some previously TRAIL-resistant cancers.…”

Section: Tnfsf Ligands Are Essential For Tnfrsf Signaling-lessons Fromentioning

confidence: 99%

“…This combination therapy proved beneficial even in some previously TRAIL-resistant cancers. The structure of the TRAIL, DR5, and the DR5 agonist antibody illustrates how the coadministration of TRAIL and the agonistic antibody achieves enhanced signaling (70). The antibody binds on the outside of each receptor linking two individual ligand-receptor complexes together into a large hexagonal network (Fig.…”

Section: Tnfsf Ligands Are Essential For Tnfrsf Signaling-lessons Fromentioning

confidence: 99%

“…We also discussed above how dominant antibodies can successfully block the binding of the ligand by firmly locking in the antiparallel dimer state of the receptor. Once activated, however, receptor trimers can be stabilized by cross-linking agonist antibodies (70). The antibodies are unable to activate the receptor; their role is to provide structural stabilization to the active signaling network initiated by ligand binding.…”

Section: Tnfrsf Signaling May Be Described By a Uniform Hexagonal Modmentioning

confidence: 99%

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Structural principles of tumor necrosis factor superfamily signaling

2018

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The tumor necrosis factor (TNF) ligand and receptor superfamilies play an important role in cell proliferation, survival, and death. Stimulating or inhibiting TNF superfamily signaling pathways is expected to have therapeutic benefit for patients with various diseases, including cancer, autoimmunity, and infectious diseases. We review our current understanding of the structure and geometry of TNF superfamily ligands, receptors, and their interactions. A trimeric ligand and three receptors, each binding at the interface of two ligand monomers, form the basic unit of signaling. Clustering of multiple receptor subunits is necessary for efficient signaling. Current reports suggest that the receptors are prearranged on the cell surface in a "nonsignaling," resting state in a large hexagonal structure of antiparallel dimers. Receptor activation requires ligand binding, and cross-linking antibodies can stabilize the receptors, thereby maintaining the active, signaling state. On the other hand, an antagonist antibody that locks receptor arrangement in antiparallel dimers effectively blocks signaling. This model may aid the design of more effective TNF signaling-targeted therapies.

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“…3A) (70), in the intracellular FasDD-FADD complex (Fig. 3B) (73), and for TRAF2 and TRAF6 oligomerization, consistent with a hexagonal lattice geometry (Fig.…”

Section: Tnfrsf Signaling May Be Described By a Uniform Hexagonal Modsupporting

confidence: 63%

Section: Tnfsf Ligands Are Essential For Tnfrsf Signaling-lessons Fromentioning

confidence: 99%

Section: Tnfsf Ligands Are Essential For Tnfrsf Signaling-lessons Fromentioning

confidence: 99%

Section: Tnfrsf Signaling May Be Described By a Uniform Hexagonal Modmentioning

confidence: 99%

See 2 more Smart Citations

Structural principles of tumor necrosis factor superfamily signaling

2018

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“…Despite the encouraging results obtained at preclinical level, no convincing anticancer activity could be recorded in patients with cancer for any of the tested approaches (1)(2)(3)(4). This could be attributed to the different sensitivity of tumors to TRAIL on one hand and to the limited activity of targeting molecules, due to the short half-life of recombinant TRAIL and the monospecificity of the agonistic antibodies (Abs), on the other (1,5).…”

Section: Introductionmentioning

confidence: 99%

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

Rivoltini

Chiodoni

Squarcina

et al. 2016

Clinical Cancer Research

163

120

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Purpose: Exosomes deliver signals to target cells and could thus be exploited as an innovative therapeutic tool. We investigated the ability of membrane TRAIL-armed exosomes to deliver proapoptotic signals to cancer cells and mediate growth inhibition in different tumor models.Experimental Methods and Results: K562 cells, transduced with lentiviral human membrane TRAIL, were used for the production of TRAIL þ exosomes, which were studied by nanoparticle tracking analysis, cytofluorimetry, immunoelectronmicroscopy, Western blot, and ELISA. In vitro, TRAIL þ exosomes induced more pronounced apoptosis (detected by Annexin V/ propidium iodide and activated caspase-3) in TRAIL-death receptor (DR)5 þ cells (SUDHL4 lymphoma and INT12 melanoma), with respect to the DR5 À DR4 þ KMS11 multiple myeloma. Intratumor injection of TRAIL þ exosomes, but not mock exosomes, induced growth inhibition of SUDHL4 (68%) and INT12 (51%), and necrosis in KMS11 tumors. After rapid blood clearance, systemically administered TRAIL þ exosomes accumulated in the liver, lungs, and spleen and homed to the tumor site, leading to a significant reduction of tumor growth (58%) in SUDHL4-bearing mice. The treatment of INT12-bearing animals promoted tumor necrosis and a not statistically significant tumor volume reduction. In KMS11-bearing mice, despite massive perivascular necrosis, no significant tumor growth inhibition was detected.Conclusions: TRAIL-armed exosomes can induce apoptosis in cancer cells and control tumor progression in vivo. Therapeutic efficacy was particularly evident in intratumor setting, while depended on tumor model upon systemic administration. Thanks to their ability to deliver multiple signals, exosomes thus represent a promising therapeutic tool in cancer.

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TRAIL‐Armed ER Nanosomes Induce Drastically Enhanced Apoptosis in Resistant Tumor in Combination with the Antagonist of IAPs (AZD5582)

Hou

Huang

et al. 2021

Adv Healthcare Materials

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Although mesenchymal stem cells (MSCs) can be engineered to deliver the TNF-related apoptosis-inducing ligand (TRAIL) as an effective anticancer therapy, the clinical application is hampered by the costly manufacturing of therapeutic MSCs. Therefore, it is needed to find an alternative cell-free therapy. In this study, TRAIL-armed endoplasmic reticulum (ER)-derived nanosomes (ERN-T) are successfully prepared with an average size of 70.6 nm in diameter from TRAIL transduced MSCs. It is demonstrated that the ERN-T is significantly more efficient for cancer cell killing than the soluble recombinant TRAIL (rTRAIL). AZD5582 is an antagonist of the inhibitors of apoptosis proteins (IAPs), and its combination with ERN-T induces strikingly enhanced apoptosis in cancerous but not normal cells. AZD5582 sensitizes resistant cancer cells to TRAIL through concomitant downregulation of IAP members like XIAP and the Bcl2 family member Mcl-1. Intravenously infused ERN-Ts accumulate in tumors for over 48 h indicating good tumor tropism and retention. The combination of ERN-T and AZD5582 drastically promotes therapeutic efficacy comparing with the cotreatment by rTRAIL and AZD5582 in a subcutaneous MDA-MB-231 xenograft tumor model. The data thus demonstrate that ERN-T can be a novel cell-free alternative to TRAIL-expressing MSC-based anticancer therapy and its efficacy can be drastically enhanced through combination with AZD5582.

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Apo2L/TRAIL and the Death Receptor 5 Agonist Antibody AMG 655 Cooperate to Promote Receptor Clustering and Antitumor Activity

Cited by 142 publications

References 53 publications

Structural principles of tumor necrosis factor superfamily signaling

Structural principles of tumor necrosis factor superfamily signaling

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

TRAIL‐Armed ER Nanosomes Induce Drastically Enhanced Apoptosis in Resistant Tumor in Combination with the Antagonist of IAPs (AZD5582)

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