Preclinical validation of a novel metastasis-inhibiting Tie1 function-blocking antibody
Abstract The angiopoietin (Ang)?Tie pathway has been intensely pursued as candidate second-generation anti-angiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2-targeting drugs is limited and failed to improve patient survival. In turn,...
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| Hauptverfasser: | , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
17 April 2020
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| In: |
EMBO molecular medicine
Year: 2020, Jahrgang: 12, Heft: 6 |
| ISSN: | 1757-4684 |
| DOI: | 10.15252/emmm.201911164 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.15252/emmm.201911164 Verlag, lizenzpflichtig, Volltext: https://www.embopress.org/doi/full/10.15252/emmm.201911164 
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| Verfasserangaben: | Mahak Singhal, Nicolas Gengenbacher, Silvia La Porta, Stephanie Gehrs, Jingjing Shi, Miki Kamiyama, Diane M Bodenmiller, Anthony Fischl, Benjamin Schieb, Eva Besemfelder, Sudhakar Chintharlapalli & Hellmut G Augustin |
| Zusammenfassung: | Abstract The angiopoietin (Ang)?Tie pathway has been intensely pursued as candidate second-generation anti-angiogenic target. While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2-targeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 remains therapeutically unexplored, although its endothelial-specific genetic deletion has previously been shown to result in a strong reduction in metastatic growth. Here, we report a novel Tie1 function-blocking antibody (AB-Tie1-39), which suppressed postnatal retinal angiogenesis. During primary tumor growth, neoadjuvant administration of AB-Tie1-39 strongly impeded systemic metastasis. Furthermore, the administration of AB-Tie1-39 in a perioperative therapeutic window led to a significant survival advantage as compared to control-IgG-treated mice. Additional in vivo experimental metastasis and in vitro transmigration assays concurrently revealed that AB-Tie1-39 treatment suppressed tumor cell extravasation at secondary sites. Taken together, the data phenocopy previous genetic work in endothelial Tie1 KO mice and thereby validate AB-Tie1-39 as a Tie1 function-blocking antibody. The study establishes Tie1 as a therapeutic target for metastasis in a perioperative or neoadjuvant setting. |
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| Beschreibung: | Gesehen am 05.10.2020 |
| Beschreibung: | Online Resource |
| ISSN: | 1757-4684 |
| DOI: | 10.15252/emmm.201911164 |