[News Article]PharmAbcine, AACR Annual Meeting 2020 Online Planner
[News Article]PharmAbcine, AACR Annual Meeting 2020 Online Planner
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A novel anti-Tie2 antibody stabilized vessel and
increased tumor infiltrated lymphocyte
Background: Tie2 acts as cell-surface receptor for Ang1/Ang2 and regulates angiogenesis, endothelial cell survival, proliferation, migration, as well as maintenance of vascular quiescence. Especially, Ang1-Tie2 signaling pathway has been known to promote blood vessel maturation and stabilization.
Methods: We have developed a series of novel human IgG monoclonal antibody that binds to human-TIE2 with a high affinity (Kd ~0.1 nM). The antibody binds to human TIE2 extracellular domain and activates its associated function in a ligand independent way. The mode of action was studied in vitro with human umbilical vein endothelial cells (HUVEC) and animal models. The vessel stabilization was investigated with laser induced choroidal neovascularization (CNV). The effect on tumor infiltrated lymphocyte was also studied in mouse colon cancer model.
Results: Anti-Tie2 antibody increased human endothelial cell migration like Ang1 and inhibited VEGF-induced vascular leakage, contributing to vessel normalization. It binds to Tie2 in a ligand independent way and thus it can stabilize vessel as an agonist. Both p-VEGFR and p-VE-Cadherin levels are also significantly decreased on VEGF-induced VEGFR signaling pathway by anti-Tie2 antibody, suggesting that it can maintain cell to cell junction. The vessel stabilization effect was demonstrated in a mouse model of laser induced CNV. Moreover, in syngeneic CT26 mouse models, anti-Tie2 antibody showed anti-tumor effect in which it significantly reduced the tumor growth and synergistically when it combined with anti PD-1 antibody. The tumor infiltrating lymphocytes were increased in CT26 tumor, especially CD8+ T cells and MDSC when anti-Tie2 was administered.
Conclusion: We developed active vessels stabilizer targeting Tie2, having an effect of vessel stabilization in a ligand independent way. It inhibited VEGF-induced vascular leakage through decrease of p-VEGFR and VE-cadherin. This active vessel stabilizer could help deliver drug and lymphocyte into the TME. The therapeutic efficacy of immune checkpoint inhibitors can be increased when it combined with this active vessel stabilizer. Thus, this active vessel stabilizer can change cold tumor into hot tumor.
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