title: Tyrosine kinase blocking collagen IV-derived peptide suppresses ocular neovascularization and vascular leakage.
abstract: Vascular endothelial growth factor (VEGF)-neutralizing proteins provide benefit in several retinal and choroidal vascular diseases, but some patients still experience suboptimal outcomes, and the need for frequent intraocular injections is a barrier to good outcomes. A mimetic peptide derived from collagen IV, AXT107, suppressed subretinal neovascularization (NV) in two mouse models predictive of effects in neovascular age-related macular degeneration (NVAMD) and inhibited retinal NV in a model predictive of effects in ischemic retinopathies. A combination of AXT107 and the current treatment aflibercept suppressed subretinal NV better than either agent alone. Furthermore, AXT107 caused regression of choroidal NV. AXT107 reduced the VEGF-induced vascular leakage that underlies macular edema in ischemic retinopathies and NVAMD. In rabbit eyes, which are closer to the size of human eyes, intraocular injection of AXT107 significantly reduced VEGF-induced vascular leakage by 86% at 1 month and 70% at 2 months; aflibercept significantly reduced leakage by 69% at 1 month and did not reduce leakage at 2 months, demonstrating the longer effectiveness of AXT107. AXT107 reduced ligand-induced phosphorylation of multiple receptors: VEGFR2, c-Met, and PDGFRβ. Optimal signaling through these receptors requires complex formation with β3integrin, which was reduced by AXT107 binding to αvβ3AXT107 also reduced total VEGFR2 levels by increasing internalization, ubiquitination, and degradation. This biomimetic peptide is a sustained, multitargeted therapy that may provide advantages over intraocular injections of specific VEGF-neutralizing proteins.
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Raquel Lima E
authors.initials: RLE
authors.lastname: Silva
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yogita
authors.initials: Y
authors.lastname: Kanan
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Mirando
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ron B
authors.initials: RB
authors.lastname: Shmueli
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Valeria E
authors.initials: VE
authors.lastname: Lorenc
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Seth D
authors.initials: SD
authors.lastname: Fortmann
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Sciamanna
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|AsclepiX Therapeutics, LLC, Baltimore, MD 21211, USA.
authors.forename: Niranjan B
authors.initials: NB
authors.lastname: Pandey
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Green
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Aleksander S
authors.initials: AS
authors.lastname: Popel
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D016475:3T3 Cells; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D020256:Choroidal Neovascularization / Q000188:drug therapy; D024141:Collagen Type IV / Q000627:therapeutic use*; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008024:Ligands; D008268:Macular Degeneration / Q000188:drug therapy*; D008269:Macular Edema / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000627:therapeutic use; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D012160:Retina / Q000473:pathology; D015861:Retinal Neovascularization / Q000188:drug therapy*; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D024141:Collagen Type IV; D039302:Integrin alphaVbeta3; D008024:Ligands; D010455:Peptides; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2