Anti-angiogenic collagen IV-derived peptide target engagement with αvβ3 and α5β1 in ocular neovascularization models

AXT107, a collagen-derived peptide that binds integrins αvβ3 and α5β1 with high affinity, suppresses vascular endothelial growth factor (VEGF) signaling, promotes angiopoietin 2-induced Tie2 activation, and suppresses neovascularization (NV) and vascular leakage. Immunohistochemical staining for αvβ...

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Bibliographic Details
Published in:iScience 2023-02, Vol.26 (2), p.106078-106078, Article 106078
Main Authors: Lima e Silva, Raquel, Mirando, Adam C., Tzeng, Stephany Y., Green, Jordan J., Popel, Aleksander S., Pandey, Niranjan B., Campochiaro, Peter A.
Format: Article
Language:English
Subjects:
Biological sciences
Cell biology
Molecular biology
Neuroscience
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Summary:AXT107, a collagen-derived peptide that binds integrins αvβ3 and α5β1 with high affinity, suppresses vascular endothelial growth factor (VEGF) signaling, promotes angiopoietin 2-induced Tie2 activation, and suppresses neovascularization (NV) and vascular leakage. Immunohistochemical staining for αvβ3 and α5β1 was markedly increased in NV compared with normal retinal vessels. After intravitreous injection of AXT107, there was no staining with an anti-AXT107 antibody on normal vessels but robust staining of NV that co-localized with αvβ3 and α5β1. Likewise, after intravitreous injection, fluorescein amidite-labeled AXT107 co-localized with αvβ3 and α5β1 on NV but not normal vessels. AXT107 also co-localized with αv and α5 at cell-cell junctions of human umbilical vein endothelial cells (HUVECs). AXT107-integrin binding was demonstrated by ex vivo cross-linking/pull-down experiments. These data support the hypothesis that AXT107 therapeutic activity is mediated through binding αvβ3 and α5β1 which are markedly upregulated on endothelial cells in NV providing selective targeting of diseased vessels which has therapeutic and safety benefits. [Display omitted] •Expression of integrins αvβ3 and α5β1 is increased on pathologic retinal vessels•AXT107 peptide and integrins αvβ3 and α5β1 co-localize on pathologic retinal vessels•AXT107-integrin interactions occur predominantly at cell-cell junctions•AXT107 peptide cross-links with integrins αvβ3 and α5β1 in hypoxic retinas Biological sciences; Molecular biology; Neuroscience; Cell biology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2023.106078