Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin
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 rem...
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/9/810 |
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| author | Simon Hauri Paulina Jakubiak Matthias Fueth Stefan Dengl Sara Belli Rubén Alvarez-Sánchez Antonello Caruso |
| author_facet | Simon Hauri Paulina Jakubiak Matthias Fueth Stefan Dengl Sara Belli Rubén Alvarez-Sánchez Antonello Caruso |
| author_sort | Simon Hauri |
| collection | DOAJ |
| description | 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 <sup>3</sup>H-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. |
| first_indexed | 2024-03-10T16:47:32Z |
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| id | doaj.art-2423a8e975de4e188560c9ef798fb2e5 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T16:47:32Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-2423a8e975de4e188560c9ef798fb2e52023-11-20T11:26:32ZengMDPI AGPharmaceutics1999-49232020-08-0112981010.3390/pharmaceutics12090810Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular AlbuminSimon Hauri0Paulina Jakubiak1Matthias Fueth2Stefan Dengl3Sara Belli4Rubén Alvarez-Sánchez5Antonello Caruso6Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, SwitzerlandRoche Pharma Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, F. Hoffmann-La Roche Ltd., Nonnenwald 2, D-82377 Penzberg, GermanyRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, SwitzerlandRoche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, SwitzerlandThe 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 <sup>3</sup>H-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.https://www.mdpi.com/1999-4923/12/9/810ocular drug deliveryocular pharmacokineticshalf-life extensionalbumintherapeutic proteinssize exclusion chromatography |
| spellingShingle | Simon Hauri Paulina Jakubiak Matthias Fueth Stefan Dengl Sara Belli Rubén Alvarez-Sánchez Antonello Caruso Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin Pharmaceutics ocular drug delivery ocular pharmacokinetics half-life extension albumin therapeutic proteins size exclusion chromatography |
| title | Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin |
| title_full | Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin |
| title_fullStr | Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin |
| title_full_unstemmed | Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin |
| title_short | Understanding the Half-Life Extension of Intravitreally Administered Antibodies Binding to Ocular Albumin |
| title_sort | understanding the half life extension of intravitreally administered antibodies binding to ocular albumin |
| topic | ocular drug delivery ocular pharmacokinetics half-life extension albumin therapeutic proteins size exclusion chromatography |
| url | https://www.mdpi.com/1999-4923/12/9/810 |
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