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Ian R Catchpole, Peter Adamson, Thomas Wilde, Eric Dobrzynski, Caroline Sychertz, Rodd Polsky, Richard Haworth, Chi-Man Tang, Jos Smal, Judith Van der Zwan; Six months effective ocular drug levels and protection against laser CNV in a cynomolgus monkey after a single ocular administration of a biodegradable microsphere delivery system releasing a highly potent anti-VEGF domain antibody based molecule.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1498.
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© ARVO (1962-2015); The Authors (2016-present)
A novel highly potent anti-vascular epithelial growth factor, (VEGF), biologic and a compatible delivery system were co-developed with the aim of generating a product to protect against wet age-related macular degeneration (AMD) over six months from a single intravitreal (IVT) injection.
The biologic anti—VEGF molecule is dimeric, each monomer contains two different anti-VEGF domain antibodies attached via linkers to a human IgG1 Fc domain: ‘a dual dAb molecule’. The delivery system is based upon microspheres of a specific PolyActive (TM): PEG-polybutylphthalate hydrogel co-polymer. The molecule was evaluated both in vitro for potency against VEGF and in vivo in ocular efficacy models. The dual dAb was encapsulated into PolyActive microspheres and tested for its ability to be released and maintain activity over 12 months in vitro. The system was evaluated for release of an effective pre-specified trough concentration in rabbit and monkey eyes over 6 months and its ability to protect in a cynomolgus monkey laser choroidal neovascularisation, (CNV), model when dosed via a single injection 6 months prior to laser initiation.
The molecule is highly potent with a lower EC50 than Eylea for inhibition of VEGF in receptor binding assays (RBA) and it captures two VEGF dimers per molecule; a stoichiometry which exceeds that of Eylea.. The molecule retains activity on release from PolyActive microparticles over 6-12 months in vitro maintaining > potency cf. Eylea in VEGF RBAs for at least 6 months. When delivered in vivo via a single IVT injection, functional molecule can be released over at least 6 months in both rabbit and monkey eyes, and sufficient effective drug is released to protect cynomolgus monkey against laser-induced grade IV CNV lesions at 6 months post-dosing.
This is the first work demonstrating proof of concept for combined delivery of a potent anti-VEGF molecule within a sustained-release system being able to protect in a pre-clinical primate model of wet AMD and achieving a 6 monthly duration of efficacy.
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