Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentration
Monoclonal antibody therapeutics is a massively growing field. Progress in providing monoclonal antibody therapeutics to treat brain disorders is complicated, due to the impermeability of the blood-brain barrier (BBB) to large macromolecular structures. To date, the most successful approach for deli...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Neurotherapeutics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S187874792400179X |
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| author | Andrés de la Rosa Nicole G. Metzendorf Jonathan Efverström Ana Godec Dag Sehlin Jamie Morrison Greta Hultqvist |
| author_facet | Andrés de la Rosa Nicole G. Metzendorf Jonathan Efverström Ana Godec Dag Sehlin Jamie Morrison Greta Hultqvist |
| author_sort | Andrés de la Rosa |
| collection | DOAJ |
| description | Monoclonal antibody therapeutics is a massively growing field. Progress in providing monoclonal antibody therapeutics to treat brain disorders is complicated, due to the impermeability of the blood-brain barrier (BBB) to large macromolecular structures. To date, the most successful approach for delivering antibody therapeutics to the brain is by targeting the transferrin receptor (TfR) using anti-TfR BBB shuttles, with the 8D3 antibody being one of the most extensively studied in the field. The strategy of fine-tuning TfR binding affinity has shown promise, with previous results showing an improved brain delivery of bivalent 8D3-BBB constructs. In the current study, a fine-tuning TfR affinity strategy has been employed to improve single-chain variable fragment (scFv) 8D3 (scFv8D3) affinity mutants. Initially, in silico protein-protein docking analysis was performed to identify amino acids (AAs) likely to contribute to 8D3s TfR binding affinity. Mutating the identified AAs resulted in decreased TfR binding affinity, increased blood half-life and increased brain concentration. As monovalent BBB shuttles are seemingly superior for delivering antibodies at therapeutically relevant doses, our findings and approach may be relevant for optimizing brain delivery. |
| format | Article |
| id | doaj-art-48d7637850ca487fa78cba58894a8166 |
| institution | Kabale University |
| issn | 1878-7479 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurotherapeutics |
| spelling | doaj-art-48d7637850ca487fa78cba58894a81662025-02-01T04:11:52ZengElsevierNeurotherapeutics1878-74792025-01-01221e00492Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentrationAndrés de la Rosa0Nicole G. Metzendorf1Jonathan Efverström2Ana Godec3Dag Sehlin4Jamie Morrison5Greta Hultqvist6Department of Pharmacy, Uppsala University, Uppsala, SwedenDepartment of Pharmacy, Uppsala University, Uppsala, SwedenDepartment of Pharmacy, Uppsala University, Uppsala, SwedenDepartment of Pharmacy, Uppsala University, Uppsala, SwedenDepartment of Public Health and Caring Sciences, Uppsala University, Uppsala, SwedenDepartment of Pharmacy, Uppsala University, Uppsala, SwedenDepartment of Pharmacy, Uppsala University, Uppsala, Sweden; Corresponding author.Monoclonal antibody therapeutics is a massively growing field. Progress in providing monoclonal antibody therapeutics to treat brain disorders is complicated, due to the impermeability of the blood-brain barrier (BBB) to large macromolecular structures. To date, the most successful approach for delivering antibody therapeutics to the brain is by targeting the transferrin receptor (TfR) using anti-TfR BBB shuttles, with the 8D3 antibody being one of the most extensively studied in the field. The strategy of fine-tuning TfR binding affinity has shown promise, with previous results showing an improved brain delivery of bivalent 8D3-BBB constructs. In the current study, a fine-tuning TfR affinity strategy has been employed to improve single-chain variable fragment (scFv) 8D3 (scFv8D3) affinity mutants. Initially, in silico protein-protein docking analysis was performed to identify amino acids (AAs) likely to contribute to 8D3s TfR binding affinity. Mutating the identified AAs resulted in decreased TfR binding affinity, increased blood half-life and increased brain concentration. As monovalent BBB shuttles are seemingly superior for delivering antibodies at therapeutically relevant doses, our findings and approach may be relevant for optimizing brain delivery.http://www.sciencedirect.com/science/article/pii/S187874792400179XBlood brain barrierTransporterAntibodiesAffinityMonovalent |
| spellingShingle | Andrés de la Rosa Nicole G. Metzendorf Jonathan Efverström Ana Godec Dag Sehlin Jamie Morrison Greta Hultqvist Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentration Neurotherapeutics Blood brain barrier Transporter Antibodies Affinity Monovalent |
| title | Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentration |
| title_full | Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentration |
| title_fullStr | Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentration |
| title_full_unstemmed | Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentration |
| title_short | Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentration |
| title_sort | lowering the affinity of single chain monovalent bbb shuttle scfc scfv8d3 prolongs its half life and increases brain concentration |
| topic | Blood brain barrier Transporter Antibodies Affinity Monovalent |
| url | http://www.sciencedirect.com/science/article/pii/S187874792400179X |
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