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Open AccessArticle

Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin

1
Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland
2
Roche Pharma Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, F. Hoffmann-La Roche Ltd., Nonnenwald 2, D-82377 Penzberg, Germany
*
Author to whom correspondence should be addressed.
Current address: Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
Pharmaceutics 2020, 12(9), 810; https://doi.org/10.3390/pharmaceutics12090810
Received: 10 July 2020 / Revised: 13 August 2020 / Accepted: 20 August 2020 / Published: 26 August 2020
(This article belongs to the Special Issue Ophthalmic Drug Delivery)
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. View Full-Text
Keywords: ocular drug delivery; ocular pharmacokinetics; half-life extension; albumin; therapeutic proteins; size exclusion chromatography ocular drug delivery; ocular pharmacokinetics; half-life extension; albumin; therapeutic proteins; size exclusion chromatography
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MDPI and ACS Style

Hauri, S.; Jakubiak, P.; Fueth, M.; Dengl, S.; Belli, S.; Alvarez-Sánchez, R.; Caruso, A. Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin. Pharmaceutics 2020, 12, 810. https://doi.org/10.3390/pharmaceutics12090810

AMA Style

Hauri S, Jakubiak P, Fueth M, Dengl S, Belli S, Alvarez-Sánchez R, Caruso A. Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin. Pharmaceutics. 2020; 12(9):810. https://doi.org/10.3390/pharmaceutics12090810

Chicago/Turabian Style

Hauri, Simon; Jakubiak, Paulina; Fueth, Matthias; Dengl, Stefan; Belli, Sara; Alvarez-Sánchez, Rubén; Caruso, Antonello. 2020. "Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin" Pharmaceutics 12, no. 9: 810. https://doi.org/10.3390/pharmaceutics12090810

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