Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies®
Nanobodies are antigen-binding, single variable domain proteins derived from naturally-occurring, heavy chain only antibodies. They are highly soluble, stable, and can be linked to build multi-specific formats. Several Nanobodies are currently in clinical development in different therapeutic areas,...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2015-07-01
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| Series: | Antibodies |
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| Online Access: | http://www.mdpi.com/2073-4468/4/3/141 |
| _version_ | 1819085904557375488 |
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| author | Sven Hoefman Ingrid Ottevaere Judith Baumeister Maria Laura Sargentini-Maier |
| author_facet | Sven Hoefman Ingrid Ottevaere Judith Baumeister Maria Laura Sargentini-Maier |
| author_sort | Sven Hoefman |
| collection | DOAJ |
| description | Nanobodies are antigen-binding, single variable domain proteins derived from naturally-occurring, heavy chain only antibodies. They are highly soluble, stable, and can be linked to build multi-specific formats. Several Nanobodies are currently in clinical development in different therapeutic areas, for both chronic and acute applications. For the former, prolonged exposure is achieved by half-life extending moieties that target endogenous albumin, while for the latter, non-half-life extended constructs are preferable. To demonstrate the general pharmacokinetic behavior of both formats, serum levels of seven intravenously administered Nanobodies were analyzed in cynomolgus monkeys, mice or rabbits. In monkeys, the total clearance of a monomeric irrelevant Nanobody was rapid (2.0 mL/(min*kg)) and approximated the species glomerular filtration rate, indirectly suggesting that the Nanobody was mainly eliminated via the kidneys. When linked to an anti-albumin Nanobody, a 376-fold decrease in clearance was observed, resulting in a terminal half-life of 4.9 days, corresponding to the expected species albumin half-life. Similar conclusions were drawn for (non-) half-life extended mono-, bi- and trimeric Nanobodies in mice or rabbits, suggesting that these kinetic principles apply across species. Applying this knowledge to species translation and study design is crucial for successful pre-clinical development of novel therapeutic Nanobody candidates. |
| first_indexed | 2024-12-21T21:11:46Z |
| format | Article |
| id | doaj.art-7f0967633ca64b7baa626d48f6ecc982 |
| institution | Directory Open Access Journal |
| issn | 2073-4468 |
| language | English |
| last_indexed | 2024-12-21T21:11:46Z |
| publishDate | 2015-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibodies |
| spelling | doaj.art-7f0967633ca64b7baa626d48f6ecc9822022-12-21T18:50:07ZengMDPI AGAntibodies2073-44682015-07-014314115610.3390/antib4030141antib4030141Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies®Sven Hoefman0Ingrid Ottevaere1Judith Baumeister2Maria Laura Sargentini-Maier3Ablynx N.V., Technologiepark 21, 9052 Zwijnaarde, BelgiumAblynx N.V., Technologiepark 21, 9052 Zwijnaarde, BelgiumAblynx N.V., Technologiepark 21, 9052 Zwijnaarde, BelgiumAblynx N.V., Technologiepark 21, 9052 Zwijnaarde, BelgiumNanobodies are antigen-binding, single variable domain proteins derived from naturally-occurring, heavy chain only antibodies. They are highly soluble, stable, and can be linked to build multi-specific formats. Several Nanobodies are currently in clinical development in different therapeutic areas, for both chronic and acute applications. For the former, prolonged exposure is achieved by half-life extending moieties that target endogenous albumin, while for the latter, non-half-life extended constructs are preferable. To demonstrate the general pharmacokinetic behavior of both formats, serum levels of seven intravenously administered Nanobodies were analyzed in cynomolgus monkeys, mice or rabbits. In monkeys, the total clearance of a monomeric irrelevant Nanobody was rapid (2.0 mL/(min*kg)) and approximated the species glomerular filtration rate, indirectly suggesting that the Nanobody was mainly eliminated via the kidneys. When linked to an anti-albumin Nanobody, a 376-fold decrease in clearance was observed, resulting in a terminal half-life of 4.9 days, corresponding to the expected species albumin half-life. Similar conclusions were drawn for (non-) half-life extended mono-, bi- and trimeric Nanobodies in mice or rabbits, suggesting that these kinetic principles apply across species. Applying this knowledge to species translation and study design is crucial for successful pre-clinical development of novel therapeutic Nanobody candidates.http://www.mdpi.com/2073-4468/4/3/141nanobodiespharmacokineticsalbuminhalf-life extensionpre-clinical |
| spellingShingle | Sven Hoefman Ingrid Ottevaere Judith Baumeister Maria Laura Sargentini-Maier Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies® Antibodies nanobodies pharmacokinetics albumin half-life extension pre-clinical |
| title | Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies® |
| title_full | Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies® |
| title_fullStr | Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies® |
| title_full_unstemmed | Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies® |
| title_short | Pre-Clinical Intravenous Serum Pharmacokinetics of Albumin Binding and Non-Half-Life Extended Nanobodies® |
| title_sort | pre clinical intravenous serum pharmacokinetics of albumin binding and non half life extended nanobodies r |
| topic | nanobodies pharmacokinetics albumin half-life extension pre-clinical |
| url | http://www.mdpi.com/2073-4468/4/3/141 |
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