Abstract
The burden associated with frequent injections of current intravitreal (IVT) therapeutics may be reduced by long-acting delivery strategies. Binding to serum albumin has been shown to extend the ocular half-life in rabbits, however, the underlying molecular mechanisms and translational relevance remain unclear. The aim of this work was to characterize the in vitro and in vivo formation of complexes between human serum albumin (HSA) and an antigen-binding fragment of a rabbit antibody linked to an anti-HSA nanobody (FabA). The ocular and systemic pharmacokinetics of 3H-labeled FabA (0.05 mg/eye IVT) co-formulated with HSA (1 and 15 nmol/eye) were assessed in Dutch belted rabbits. Next, FabA was incubated in vitreous samples from cynomolgus monkeys and human donors (healthy and diseased) supplemented with species-specific serum albumin. Finally, the FabA-albumin complexes formed in vitro and in vivo were analyzed by radio-size exclusion chromatography. A 3-fold increase in FabA vitreal exposure and half-life was observed in rabbits co-administered with 15 nmol HSA compared to 1 nmol and a control arm. The different pharmacokinetic behavior was explained with the formation of higher molecular weight FabA–albumin complexes. The analysis of vitreous samples revealed the existence of predominantly 1:1 complexes at endogenous or low concentrations of supplemented albumin. A shift towards 1:2 complexes was observed with increasing albumin concentrations. Overall, these results suggest that endogenous vitreal albumin concentrations are insufficient for half-life extension and warrant supplementation in the dosing formulation.
Highlights
As the number of patients with vision-threatening conditions has been steadily increasing in recent years, largely driven by the growth and ageing of the world’s population [1], so have the efforts directed at finding novel treatments
The development of anti-vascular endothelial growth factor (VEGF) therapeutics has transformed the management of neovascular age-related macular degeneration, diabetic retinopathy (DR) and diabetic macular edema (DME) [2,3]
For the vitreous humor (VH) samples of the 15:1 molar ratio group, the radio signal shifted to the higher molecular weight (MW) species greater than 150 kDa, consistent with the MW of a 1:2 complex of about 180 kDa (Figure 3B). These findings suggest the formation of higher stoichiometry complexes because of the higher albumin concentration that could be responsible for the ocular half-life extension observed in vivo
Summary
As the number of patients with vision-threatening conditions has been steadily increasing in recent years, largely driven by the growth and ageing of the world’s population [1], so have the efforts directed at finding novel treatments. The development of anti-vascular endothelial growth factor (VEGF) therapeutics has transformed the management of neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR) and diabetic macular edema (DME) [2,3]. IVT injections are invasive and can pose a significant medical, psychological, and financial burden on patients and healthcare systems alike. For these reasons, treatment options with less frequent dosing regimens are desirable, potentially improving outcomes and compliance [11]
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