[Title]
An agonistic anti-Tie2 antibody suppresses the normal-to-tumor vascular transition in the glioblastoma invasion zone

[Author] 
Eunhyeong Lee1,11, Eun-Ah Lee2,11, Eunji Kong1 , Haemin Chon1 , Melissa Llaiqui-Condori1 , Cheon Ho Park2 , Beom Yong Park2 , Nu Ri Kang2 , Jin-San Yoo2 , Hyun-Soo Lee3 , Hyung-Seok Kim4 , Sung-Hong Park 3 , Seung-Won Choi 5 , Dietmar Vestweber6 , Jeong Ho Lee 1,7,8, Pilhan Kim 1,9,10, Weon Sup Lee2 and Injune Kim 1,7

1 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
2 R&D Center, PharmAbcine Inc., Daejeon 34047, Republic of Korea.
3 Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Republic of Korea.
4 Department of Forensic Medicine, Chonnam National University Medical School, Gwangju 61463, Republic of Korea.
5 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, Republic of Korea.
6 Max Planck Institute for Molecular Biomedicine, D-48149 Muenster, Germany.
7 BioMedical Research Center, KAIST, Daejeon 34141, Republic of Korea.
8 SoVarGen, Inc., Daejeon 34051, Republic of Korea.
9 Graduate School of Nanoscience and Technology, Daejeon 34141, Republic of Korea.
10 KI for Health Science and Technology, KAIST, Daejeon 34141, Republic of Korea.
11 These authors contributed equally: Eunhyeong Lee, Eun-Ah Lee. 

[Journal] 
Experimental & Molecular Medicine volume 55, pages470–484 (2023)

[Abstract]
Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffuse tumor infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to the tumor core was also found in human GBM. The levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) showed a spatial correlation with the extent of vascular abnormalities spanning the tumor-invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confirming the role of VEGF-VEGFR2 signaling in the invasion-associated vascular transition. As angiopoietin-2 (ANGPT2) was expressed in only a portion of the central tumor vessels, we developed a ligand-independent tunica interna endothelial cell kinase 2 (Tie2)-activating antibody that can result in Tie2 phosphorylation in vivo. This agonistic anti-Tie2 antibody effectively normalized the vasculature in both the tumor periphery and tumor center, similar to the effects of VEGFR2 blockade. Mechanistically, this antibody-based Tie2 activation induced VE-PTP-mediated VEGFR2 dephosphorylation in vivo. Thus, our study reveals that the normal-to-tumor vascular transition is spatiotemporally associated with GBM invasion and may be controlled by Tie2 activation via a novel mechanism of action.