Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics
The blood-brain barrier (BBB), while being the gatekeeper of the central nervous system (CNS), is a bottleneck for the treatment of neurological diseases. Unfortunately, most of the biologicals do not reach their brain targets in sufficient quantities. The antibody targeting of receptor-mediated tra...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/6/1748 |
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| author | Laura Rué Tom Jaspers Isabelle M. S. Degors Sam Noppen Dominique Schols Bart De Strooper Maarten Dewilde |
| author_facet | Laura Rué Tom Jaspers Isabelle M. S. Degors Sam Noppen Dominique Schols Bart De Strooper Maarten Dewilde |
| author_sort | Laura Rué |
| collection | DOAJ |
| description | The blood-brain barrier (BBB), while being the gatekeeper of the central nervous system (CNS), is a bottleneck for the treatment of neurological diseases. Unfortunately, most of the biologicals do not reach their brain targets in sufficient quantities. The antibody targeting of receptor-mediated transcytosis (RMT) receptors is an exploited mechanism that increases brain permeability. We previously discovered an anti-human transferrin receptor (TfR) nanobody that could efficiently deliver a therapeutic moiety across the BBB. Despite the high homology between human and cynomolgus TfR, the nanobody was unable to bind the non-human primate receptor. Here we report the discovery of two nanobodies that were able to bind human and cynomolgus TfR, making these nanobodies more clinically relevant. Whereas nanobody BBB00515 bound cynomolgus TfR with 18 times more affinity than it did human TfR, nanobody BBB00533 bound human and cynomolgus TfR with similar affinities. When fused with an anti-beta-site amyloid precursor protein cleaving enzyme (BACE1) antibody (1A11AM), each of the nanobodies was able to increase its brain permeability after peripheral injection. A 40% reduction of brain Aβ<sub>1–40</sub> levels could be observed in mice injected with anti-TfR/BACE1 bispecific antibodies when compared to vehicle-injected mice. In summary, we found two nanobodies that could bind both human and cynomolgus TfR with the potential to be used clinically to increase the brain permeability of therapeutic biologicals. |
| first_indexed | 2024-03-11T02:02:09Z |
| format | Article |
| id | doaj.art-880fe005eef2441ca5eae8db705ec7c9 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T02:02:09Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-880fe005eef2441ca5eae8db705ec7c92023-11-18T12:05:58ZengMDPI AGPharmaceutics1999-49232023-06-01156174810.3390/pharmaceutics15061748Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of BiologicsLaura Rué0Tom Jaspers1Isabelle M. S. Degors2Sam Noppen3Dominique Schols4Bart De Strooper5Maarten Dewilde6Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, BelgiumLaboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, BelgiumVIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, BelgiumLaboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, 3000 Leuven, BelgiumLaboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, 3000 Leuven, BelgiumVIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, BelgiumLaboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, BelgiumThe blood-brain barrier (BBB), while being the gatekeeper of the central nervous system (CNS), is a bottleneck for the treatment of neurological diseases. Unfortunately, most of the biologicals do not reach their brain targets in sufficient quantities. The antibody targeting of receptor-mediated transcytosis (RMT) receptors is an exploited mechanism that increases brain permeability. We previously discovered an anti-human transferrin receptor (TfR) nanobody that could efficiently deliver a therapeutic moiety across the BBB. Despite the high homology between human and cynomolgus TfR, the nanobody was unable to bind the non-human primate receptor. Here we report the discovery of two nanobodies that were able to bind human and cynomolgus TfR, making these nanobodies more clinically relevant. Whereas nanobody BBB00515 bound cynomolgus TfR with 18 times more affinity than it did human TfR, nanobody BBB00533 bound human and cynomolgus TfR with similar affinities. When fused with an anti-beta-site amyloid precursor protein cleaving enzyme (BACE1) antibody (1A11AM), each of the nanobodies was able to increase its brain permeability after peripheral injection. A 40% reduction of brain Aβ<sub>1–40</sub> levels could be observed in mice injected with anti-TfR/BACE1 bispecific antibodies when compared to vehicle-injected mice. In summary, we found two nanobodies that could bind both human and cynomolgus TfR with the potential to be used clinically to increase the brain permeability of therapeutic biologicals.https://www.mdpi.com/1999-4923/15/6/1748nanobodyVHHtransferrin receptorblood-brain barrierreceptor-mediated transcytosis |
| spellingShingle | Laura Rué Tom Jaspers Isabelle M. S. Degors Sam Noppen Dominique Schols Bart De Strooper Maarten Dewilde Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics Pharmaceutics nanobody VHH transferrin receptor blood-brain barrier receptor-mediated transcytosis |
| title | Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics |
| title_full | Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics |
| title_fullStr | Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics |
| title_full_unstemmed | Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics |
| title_short | Novel Human/Non-Human Primate Cross-Reactive Anti-Transferrin Receptor Nanobodies for Brain Delivery of Biologics |
| title_sort | novel human non human primate cross reactive anti transferrin receptor nanobodies for brain delivery of biologics |
| topic | nanobody VHH transferrin receptor blood-brain barrier receptor-mediated transcytosis |
| url | https://www.mdpi.com/1999-4923/15/6/1748 |
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