Single domain antibody-scFv conjugate targeting amyloid β and TfR penetrates the blood–brain barrier and interacts with amyloid β
Neurodegenerative diseases such as Alzheimer’s disease (AD) pose substantial challenges to patients and health-care systems, particularly in countries with aging populations. Immunotherapies, including the marketed antibodies lecanemab (Leqembi®) and donanemab (KisunlaTM), offer promise but face hur...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2410968 |
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| author | Rebecca Faresjö Elisabet O. Sjöström Tiffany Dallas Magnus M. Berglund Jonas Eriksson Dag Sehlin Stina Syvänen |
| author_facet | Rebecca Faresjö Elisabet O. Sjöström Tiffany Dallas Magnus M. Berglund Jonas Eriksson Dag Sehlin Stina Syvänen |
| author_sort | Rebecca Faresjö |
| collection | DOAJ |
| description | Neurodegenerative diseases such as Alzheimer’s disease (AD) pose substantial challenges to patients and health-care systems, particularly in countries with aging populations. Immunotherapies, including the marketed antibodies lecanemab (Leqembi®) and donanemab (KisunlaTM), offer promise but face hurdles due to limited delivery across the blood–brain barrier (BBB). This limitation necessitates high doses, resulting in increased costs and a higher risk of side effects. This study explores transferrin receptor (TfR)-binding camelid single-domain antibodies (VHHs) for facilitated brain delivery. We developed and evaluated fusion proteins (FPs) combining VHHs with human IgG Fc domains or single-chain variable fragments (scFvs) of the anti-amyloid-beta (Aβ) antibody 3D6. In vitro assessments showed varying affinities of the FPs for TfR. In vivo evaluations indicated that specific VHH-Fc and VHH-scFv fusions reached significant brain concentrations, emphasizing the importance of optimal TfR binding affinities. The VHH-scFv fusions were further investigated in mouse models with Aβ pathology, showing higher retention compared to wild-type mice without Aβ pathology. Our findings suggest that these novel VHH-based FPs hold potential for therapeutic and diagnostic applications in AD, providing a strategy to overcome BBB limitations and enhance brain targeting of antibody-based treatments. Furthermore, our results suggest that a given bispecific TfR-binding fusion format has a window of “optimal” affinity where parenchymal delivery is adequate, while blood pharmacokinetics aligns with the desired application of the fusion protein. |
| format | Article |
| id | doaj-art-041fd12ae7354b68b4c4b27fadafe24b |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-041fd12ae7354b68b4c4b27fadafe24b2025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2410968Single domain antibody-scFv conjugate targeting amyloid β and TfR penetrates the blood–brain barrier and interacts with amyloid βRebecca Faresjö0Elisabet O. Sjöström1Tiffany Dallas2Magnus M. Berglund3Jonas Eriksson4Dag Sehlin5Stina Syvänen6Department of Public Health and Caring Sciences, Uppsala University, Uppsala, SwedenDepartment of Public Health and Caring Sciences, Uppsala University, Uppsala, SwedenDepartment of Public Health and Caring Sciences, Uppsala University, Uppsala, SwedenKey2Brain AB, Solna, SwedenPET Centre, Uppsala University Hospital, Uppsala, SwedenDepartment of Public Health and Caring Sciences, Uppsala University, Uppsala, SwedenDepartment of Public Health and Caring Sciences, Uppsala University, Uppsala, SwedenNeurodegenerative diseases such as Alzheimer’s disease (AD) pose substantial challenges to patients and health-care systems, particularly in countries with aging populations. Immunotherapies, including the marketed antibodies lecanemab (Leqembi®) and donanemab (KisunlaTM), offer promise but face hurdles due to limited delivery across the blood–brain barrier (BBB). This limitation necessitates high doses, resulting in increased costs and a higher risk of side effects. This study explores transferrin receptor (TfR)-binding camelid single-domain antibodies (VHHs) for facilitated brain delivery. We developed and evaluated fusion proteins (FPs) combining VHHs with human IgG Fc domains or single-chain variable fragments (scFvs) of the anti-amyloid-beta (Aβ) antibody 3D6. In vitro assessments showed varying affinities of the FPs for TfR. In vivo evaluations indicated that specific VHH-Fc and VHH-scFv fusions reached significant brain concentrations, emphasizing the importance of optimal TfR binding affinities. The VHH-scFv fusions were further investigated in mouse models with Aβ pathology, showing higher retention compared to wild-type mice without Aβ pathology. Our findings suggest that these novel VHH-based FPs hold potential for therapeutic and diagnostic applications in AD, providing a strategy to overcome BBB limitations and enhance brain targeting of antibody-based treatments. Furthermore, our results suggest that a given bispecific TfR-binding fusion format has a window of “optimal” affinity where parenchymal delivery is adequate, while blood pharmacokinetics aligns with the desired application of the fusion protein.https://www.tandfonline.com/doi/10.1080/19420862.2024.2410968Blood-brain barrierbrain deliverycamelid antibodyfusion proteintransferrin receptorVHH |
| spellingShingle | Rebecca Faresjö Elisabet O. Sjöström Tiffany Dallas Magnus M. Berglund Jonas Eriksson Dag Sehlin Stina Syvänen Single domain antibody-scFv conjugate targeting amyloid β and TfR penetrates the blood–brain barrier and interacts with amyloid β mAbs Blood-brain barrier brain delivery camelid antibody fusion protein transferrin receptor VHH |
| title | Single domain antibody-scFv conjugate targeting amyloid β and TfR penetrates the blood–brain barrier and interacts with amyloid β |
| title_full | Single domain antibody-scFv conjugate targeting amyloid β and TfR penetrates the blood–brain barrier and interacts with amyloid β |
| title_fullStr | Single domain antibody-scFv conjugate targeting amyloid β and TfR penetrates the blood–brain barrier and interacts with amyloid β |
| title_full_unstemmed | Single domain antibody-scFv conjugate targeting amyloid β and TfR penetrates the blood–brain barrier and interacts with amyloid β |
| title_short | Single domain antibody-scFv conjugate targeting amyloid β and TfR penetrates the blood–brain barrier and interacts with amyloid β |
| title_sort | single domain antibody scfv conjugate targeting amyloid β and tfr penetrates the blood brain barrier and interacts with amyloid β |
| topic | Blood-brain barrier brain delivery camelid antibody fusion protein transferrin receptor VHH |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2410968 |
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