| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T70067 | ||||
| Target Name | Tumor necrosis factor receptor superfamily member 10B | ||||
| Target Type | Clinical Trial |
||||
| Action against Disease Model | Conatumumab | Conat uM uMab binds to DR5, activating intracellular caspases in vitro in the presence of a cross-linker. Conat uM uMab has activity in vivo and inhibits t uMor growth in colon (Colo205 and HCT-15), lung (H2122) and pancreatic (MiaPaCa2/T2) xenograft models. Conat uM uMab also enhances the antit uMor activity of chemotherapeutics in vivo. Caspase activation in Colo205 t uMors is dose-dependent and correlated with ser uM concentrations of conat uM uMab. Increases in ser uM caspase-3/7 activity and levels of M30 (neoepitope of caspase-cleaved cytokeratin-18) are linked to activation of the extrinsic apoptotic pathway using conat uM uMab in a preclinical model. | [553020] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ile uM, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli | [553020] | |||
| References | |||||
| Ref 553020 | Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types. Cancer Biol Ther. 2010 Apr 15;9(8):618-31. Epub 2010 Apr 20. | ||||
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