Single ocular injection of a sustained-release anti-VEGF delivers 6months pharmacokinetics and efficacy in a primate laser CNV model

Autor: Justyna Korczynska, Lemy Tsikna, Zoe Hughes-Thomas, Richard Haworth, Christopher J. Roberts, John Warrack, Steven D. Sorden, Irene Papanicolaou, Rodd Polsky, Eric Dobrzynski, Edit Kurali, Timothy Streit, Thomas Wilde, Jeffery J Prusakiewicz, Brian J Christian, Peter C. Adamson, T Michael Nork, Ian Richard Catchpole, Craig Struble, Caroline Sychterz, James Walford, Chi-Man Tang, Daniel Gibson, Ruud Verrijk, Paul E. Miller, Fiona Cook, Jos Smal
Rok vydání: 2016
Předmět:
Vascular Endothelial Growth Factor A
medicine.medical_specialty
medicine.medical_treatment
Polyesters
Pharmaceutical Science
02 engineering and technology
Pharmacology
Antibodies
Article
Polyethylene Glycols
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
In vivo
medicine
Animals
Humans
Particle Size
Aflibercept
Drug Carriers
Chemistry
Growth factor
Lasers
Non-human primate eyes
021001 nanoscience & nanotechnology
Sustained-release delivery
VEGF
eye diseases
In vitro
Choroidal Neovascularization
Microspheres
Surgery
Immunoglobulin Fc Fragments
Vascular endothelial growth factor A
Drug Liberation
Macaca fascicularis
Choroidal neovascularization
Delayed-Action Preparations
Immunoglobulin G
Intravitreal Injections
030221 ophthalmology & optometry
Wet Macular Degeneration
Choroidal neovascularisation
Rabbits
Intraocular injection
medicine.symptom
0210 nano-technology
Drug carrier
medicine.drug
Zdroj: Journal of controlled release : official journal of the Controlled Release Society
ISSN: 1873-4995
Popis: A potent anti-vascular endothelial growth factor (VEGF) biologic and a compatible delivery system were co-evaluated for protection against wet age-related macular degeneration (AMD) over a 6month period following a single intravitreal (IVT) injection. The anti-VEGF molecule is dimeric, containing two different anti-VEGF domain antibodies (dAb) attached to a human IgG1 Fc region: a dual dAb. The delivery system is based on microparticles of PolyActive™ hydrogel co-polymer. The molecule was evaluated both in vitro for potency against VEGF and in ocular VEGF-driven efficacy models in vivo. The dual dAb is highly potent, showing a lower IC50 than aflibercept in VEGF receptor binding assays (RBAs) and retaining activity upon release from microparticles over 12months in vitro. Microparticles released functional dual dAb in rabbit and primate eyes over 6months at sufficient levels to protect Cynomolgus against laser-induced grade IV choroidal neovascularisation (CNV). This demonstrates proof of concept for delivery of an anti-VEGF molecule within a sustained-release system, showing protection in a pre-clinical primate model of wet AMD over 6months. Polymer breakdown and movement of microparticles in the eye may limit development of particle-based approaches for sustained release after IVT injection.
Databáze: OpenAIRE
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