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
Affiliations
Raquel Lima e Silva
Department of Ophthalmology and The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Adam C. Mirando
AsclepiX Therapeutics, Inc., Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Stephany Y. Tzeng
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jordan J. Green
Department of Ophthalmology and The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Aleksander S. Popel
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Niranjan B. Pandey
AsclepiX Therapeutics, Inc., Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Peter A. Campochiaro
Department of Ophthalmology and The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding author
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.
