Single ocular injection of a sustained-release anti-VEGF delivers 6months pharmacokinetics and efficacy in a primate laser CNV model.
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 IC50than 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.
GSK Ophthalmology, Stevenage, UK; GSK, King of Prussia, PA, USA; ProQR Therapeutics NV, Zernikedreef 9, 2333CR Leiden, The Netherlands.
Peter
P
Adamson
Drug Metabolism & Pharmacokinetics, UK; GSK, King of Prussia, PA, USA; Janssen Research & Development, PA 19002, USA.
Thomas
T
Wilde
Drug Metabolism & Pharmacokinetics, UK; GSK, King of Prussia, PA, USA.
Eric
E
Dobrzynski
Drug Metabolism & Pharmacokinetics, UK; GSK, King of Prussia, PA, USA.
Caroline
C
Sychterz
Safety Assessment, King of Prussia, PA, USA; GSK, King of Prussia, PA, USA.
Rodd
R
Polsky
Target Science Statistics, Leiden, The Netherlands; Janssen Research & Development, PA 19002, USA.
Edit
E
Kurali
Safety Assessment, King of Prussia, PA, USA; GSK Ware, UK.
Richard
R
Haworth
BioPharm Innovation, Madison, WI, USA; GSK Medicines Research Centre, Stevenage, UK; MedImmune, Granta Park, Cambridge, UK.
Chi-Man
CM
Tang
BioPharm Discovery, Madison, WI, USA; GSK Medicines Research Centre, Stevenage, UK.
Justyna
J
Korczynska
BioPharm Discovery, Madison, WI, USA; GSK Medicines Research Centre, Stevenage, UK.
Fiona
F
Cook
BioPharm Innovation, Madison, WI, USA; GSK Medicines Research Centre, Stevenage, UK.
Irene
I
Papanicolaou
BioPharm Discovery, Madison, WI, USA; GSK Medicines Research Centre, Stevenage, UK; Avacta Life Sciences, Whittlesford, Cambridge, UK.
Lemy
L
Tsikna
BioPharm Discovery, Madison, WI, USA; GSK Medicines Research Centre, Stevenage, UK.
Chris
C
Roberts
BioPharm Discovery, Madison, WI, USA; GSK Medicines Research Centre, Stevenage, UK.
Zoe
Z
Hughes-Thomas
BioPharm Process Research, Zernikedreef 9, 2333CR Leiden, The Netherlands; GSK Medicines Research Centre, Stevenage, UK.
James
J
Walford
BioPharm Process Research, Zernikedreef 9, 2333CR Leiden, The Netherlands; GSK Medicines Research Centre, Stevenage, UK.
Daniel
D
Gibson
AnalyticalSciences, Granta Park, Cambridge, UK; GSK Medicines Research Centre, Stevenage, UK.
John
J
Warrack
OctoPlus NV, Leiden, The Netherlands.
Jos
J
Smal
OctoPlus NV, Leiden, The Netherlands.
Ruud
R
Verrijk
OSOD, Madison, WI, USA.
Paul E
PE
Miller
OSOD, Madison, WI, USA; University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
T Michael
TM
Nork
Covance, Madison, WI, USA.
Jeffery
J
Prusakiewicz
Covance, Madison, WI, USA.
Timothy
T
Streit
Covance, Madison, WI, USA.
Steven
S
Sorden
Covance, Madison, WI, USA.
Craig
C
Struble
Covance, Madison, WI, USA.
Brian
B
Christian
GSK Ophthalmology, Stevenage, UK; BioPharm Innovation, Madison, WI, USA; GSK Medicines Research Centre, Stevenage, UK. Electronic address: ian.r.catchpole@gsk.com.
Ian R
IR
Catchpole
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D020256:Choroidal Neovascularization / Q000276:immunology / Q000517:prevention & control*; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D065546:Drug Liberation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D058449:Intravitreal Injections; D007834:Lasers; D008252:Macaca fascicularis; D008863:Microspheres; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011817:Rabbits; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D057135:Wet Macular Degeneration / Q000517:prevention & control
D000906:Antibodies; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011091:Polyesters; D042461:Vascular Endothelial Growth Factor A; D011092:Polyethylene Glycols
Choroidal neovascularisation; Intraocular injection; Microspheres; Non-human primate eyes; Sustained-release delivery; VEGF