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- W2242922265 abstract "e13554 Background: NGR-TNF is a new peptide-targeted agent coupling CNGRCG peptide (NGR), homing to angiogenic blood vessels, and tumor necrosis factor alpha (TNF), presently in clinical development (phase II studies in MPM, HCC and CRC). Methods: To further elucidate its mechanism of action, we studied NGR-TNF homing and downstream effects with doses comparable to those used in clinical trials. Results: Using NGR-quantum dots in vivo, NGR specifically targets the CD13 expressed in neoangiogenic vessels, sparing CD13+ normal tissues. Using CD13-specific shRNAs we showed that target cell CD13-expression is essential but not sufficient for NGR binding. For the first time, we formally demonstrated the physical interaction between NGR and CD13 by pool-down experiments using NGR-biotinylinated peptides. Although molecular characterization of the NGR-binding complex is still ongoing, microvesicles released by NGR-binding cells are able to transfer the NGR-binding capability to NGR-non-binder cells, suggesting that the binding complex associates on the target cell before NGR engages CD13. The in vivo activity of NGR-TNF may be due to target cell homing determining an increased affinity for TNF receptor (TNFR), and/or to CD13 cell signaling. Our data support the contribution of both mechanisms. First, using a recombinant tagged-human TNF as a probe along with NGR-TNF and TNF as competitors, NGR-TNF has an NGR-mediated higher affinity for TNFR than TNF. Second, in TNF-activated endothelial cells, NGR-TNF inhibits Mek, Erk1/2, and Akt, and activates caspases 3, 8, and 9, resulting in tumor endothelial cells apoptosis in vivo. Of note, these pathways are similarly activated also using NGR and TNF as separate molecules engaging CD13 and TNFR, respectively, indicating that both NGR and TNF portions contribute to the activation of signaling pathways by NGR-TNF. Conclusions: The binding of NGR to CD13 determines not only the “mere homing” of NGR-TNF but also a) the stabilization of the NGR-CD13/TNF-TNFR interaction and b) a direct effect of CD13, leading to a highly selective homing on tumor blood vessels and apoptosis of angiogenic endothelial cells in vivo, thus significantly contributing to the control of tumor growth. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MolMed MolMed" @default.
- W2242922265 created "2016-06-24" @default.
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- W2242922265 date "2010-05-20" @default.
- W2242922265 modified "2023-09-24" @default.
- W2242922265 title "Contribution of NGR and TNF portions of NGR-TNF to tumor vessel-specific homing and apoptosis in vivo." @default.
- W2242922265 doi "https://doi.org/10.1200/jco.2010.28.15_suppl.e13554" @default.
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