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

Raquel Lima E Silva; Adam C Mirando; Stephany Y Tzeng; Jordan J Green; Aleksander S Popel; Niranjan B Pandey; Peter A Campochiaro

doi:10.1016/j.isci.2023.106078

Anti-angiogenic collagen IV-derived peptide target engagement with α_vβ₃ and α₅β₁ in ocular neovascularization models

iScience. 2023 Jan 30;26(2):106078. doi: 10.1016/j.isci.2023.106078. eCollection 2023 Feb 17.

Authors

Raquel Lima E Silva^{1

2}, Adam C Mirando^{3

4}, Stephany Y Tzeng^{4

5}, Jordan J Green^{1

4

5}, Aleksander S Popel⁴, Niranjan B Pandey^{3

4}, Peter A Campochiaro^{1

2}

Affiliations

¹ Department of Ophthalmology and The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ AsclepiX Therapeutics, Inc., Baltimore, MD, USA.
⁴ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Abstract

AXT107, a collagen-derived peptide that binds integrins α_vβ₃ 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 α_vβ₃ 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 α_vβ₃ and α₅β₁. Likewise, after intravitreous injection, fluorescein amidite-labeled AXT107 co-localized with α_vβ₃ and α₅β₁ on NV but not normal vessels. AXT107 also co-localized with α_v 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 α_vβ₃ and α₅β₁ which are markedly upregulated on endothelial cells in NV providing selective targeting of diseased vessels which has therapeutic and safety benefits.

Keywords: Biological sciences; Cell biology; Molecular biology; Neuroscience.

Abstract

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