TY  - JOUR
AU  - Singhal, Mahak
AU  - Gengenbacher, Nicolas
AU  - La Porta, Silvia
AU  - Gehrs, Stephanie
AU  - Shi, Jingjing
AU  - Kamiyama, Miki
AU  - Bodenmiller, Diane M
AU  - Fischl, Anthony
AU  - Schieb, Benjamin
AU  - Besemfelder, Eva
AU  - Chintharlapalli, Sudhakar
AU  - Augustin, Hellmut
TI  - Preclinical validation of a novel metastasis-inhibiting Tie1 function-blocking antibody.
JO  - EMBO molecular medicine
VL  - 12
IS  - 6
SN  - 1757-4684
CY  - Heidelberg
PB  - EMBO Press
M1  - DKFZ-2020-00844
SP  - e11164
PY  - 2020
N1  - DKFZ-ZMBH Alliance2020 Jun 8;12(6):e11164#EA:A190#LA:A190#
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32302470
DO  - DOI:10.15252/emmm.201911164
UR  - https://inrepo02.dkfz.de/record/154523
ER  -