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

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• 作者：Peter Adamson^a ; ⁱ ; Thomas Wilde^b ; ⁱ ; Eric Dobrzynski^b ; ⁱ ; Caroline Sychterz^b ; ⁱ ; Rodd Polsky^c ; ⁱ ; Edit Kurali^d ; ⁱ ; Richard Haworth^c ; ^j ; Chi-Man Tang^e ; ^k ; Justyna Korczynska^f ; ^k ; Fiona Cook^f ; ^k ; Irene Papanicolaou^e ; ^k ; Lemy Tsikna^f ; ^k ; Chris Roberts^f ; ^k ; Zoe Hughes-Thomas^f ; ^k ; James Walford^g ; ^k ; Daniel Gibson^g ; ^k ; John Warrack^h ; ^k ; Jos Smal^l ; Ruud Verrijk^l ; Paul E. Miller^m ; T. Michael Nork^m ; ⁿ ; Jeffery Prusakiewicz^o ; Timothy Streit^o ; Steven Sorden^o ; Craig Struble^o ; Brian Christian^o ; Ian R. Catchpole^a ; ^e ; ^k ; ^{ian.r.catchpole@gsk.com}
• 关键词：VEGF ; Choroidal neovascularisation ; Sustained-release delivery ; Intraocular injection ; Microspheres ; Non-human primate eyes
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：28 December 2016
• 年：2016
• 卷：244
• 期：part_PA
• 页码：1-13
• 全文大小：2540 K
• 卷排序：244

文摘

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 6 month 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 12 months in vitro. Microparticles released functional dual dAb in rabbit and primate eyes over 6 months 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 6 months. Polymer breakdown and movement of microparticles in the eye may limit development of particle-based approaches for sustained release after IVT injection.