Abstract
Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye’s vitreous, with therapeutic antibodies and proteins. When administered to rabbit and monkey eyes, the half-life of the modified proteins is increased ∼3–4-fold relative to unmodified proteins. We further show that prototype long-acting anti-VEGF drugs (LAVAs) that include this peptide attenuate VEGF-induced retinal changes in animal models of neovascular retinal disease ∼3–4-fold longer than unmodified drugs. This approach has the potential to reduce the dosing frequency associated with retinal disease treatments.
Highlights
Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases
A feature of retinal neovascular diseases including neovascular age-related macular degeneration (AMD), diabetic macular oedema and retinal vein occlusion is that choroidal or retinal blood vessels are abnormally leaky due to a vascular endothelial growth factor (VEGF)-dependent increase in vascular permeability
An abundant blood protein, has been used as a binding target or fusion partner to prolong the systemic half-life of antibodies and proteins[7], and it has a molar abundance close to that required for a Fab drug such as ranibizumab
Summary
Identification of peptides with an affinity for hyaluronan. Hyaladherins are proteins that contain one or a few copies of a conserved structural region called a LINK domain. To enable more rapid screening, the time course of the rabbit model was shortened to 3 weeks by lowering the ranibizumab dose (the control comparator) to 5 mg per eye (105 pmol per dose) At this molar dose, ranibizumab and other control anti-VEGF drugs such as bevacizumab (an IgG), aflibercept (a receptor trap), NVS0 (a Fab) and brolucizumab (an scFv) did not substantially suppress hVEGF-A165-induced retinal vascular leakage 3 weeks post dosing. Cynomolgus monkeys (three animals per group 1⁄4 six eyes per group) received bilateral injections of equimolar doses (B5,400 pmol) of ranibizumab (263 mg) or LAVA1 (324 mg) 8 or 35 days before laser photocoagulation to induce four CNV lesions per eye. During the expression and purification of LAVA1, proteolytic degradation products were observed by SDS–polyacrylamide gel electrophoresis, reverse-phase chromatography and mass
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