Modifying antibody-FcRn interactions to increase the transport of antibodies through the blood-brain barrier
ABSTRACTThe blood-brain barrier (BBB) largely excludes antibodies from entering the central nervous system, thus limiting the potential of therapeutic antibodies to treat conditions such as neurodegenerative diseases and neuro-psychiatric disorders. Here, we demonstrate that the transport of human a...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2023-12-01
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| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2229098 |
| _version_ | 1797356296440119296 |
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| author | Jason Tien Dmitri Leonoudakis Ralitsa Petrova Vivian Trinh Tetsuya Taura Debapriya Sengupta Lisa Jo Angela Sho Yong Yun Eric Doan Anita Jamin Hussein Hallak David S. Wilson Jennifer R. Stratton |
| author_facet | Jason Tien Dmitri Leonoudakis Ralitsa Petrova Vivian Trinh Tetsuya Taura Debapriya Sengupta Lisa Jo Angela Sho Yong Yun Eric Doan Anita Jamin Hussein Hallak David S. Wilson Jennifer R. Stratton |
| author_sort | Jason Tien |
| collection | DOAJ |
| description | ABSTRACTThe blood-brain barrier (BBB) largely excludes antibodies from entering the central nervous system, thus limiting the potential of therapeutic antibodies to treat conditions such as neurodegenerative diseases and neuro-psychiatric disorders. Here, we demonstrate that the transport of human antibodies across the BBB in mice can be enhanced by modulating their interactions with the neonatal Fc receptor (FcRn). When M252Y/S254T/T246E substitutions are introduced on the antibody Fc domain, immunohistochemical assays reveal widespread distribution of the engineered antibodies throughout the mouse brain. These engineered antibodies remain specific for their antigens and retain pharmacological activity. We propose that novel brain-targeted therapeutic antibodies can be engineered to differentially engage FcRn for receptor-mediated transcytosis across the BBB in order to improve neurological disease therapeutics in the future. |
| first_indexed | 2024-03-08T14:24:35Z |
| format | Article |
| id | doaj.art-cdaf2256be904993bfc4da5093e8c198 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-03-08T14:24:35Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-cdaf2256be904993bfc4da5093e8c1982024-01-13T11:27:51ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2023.2229098Modifying antibody-FcRn interactions to increase the transport of antibodies through the blood-brain barrierJason Tien0Dmitri Leonoudakis1Ralitsa Petrova2Vivian Trinh3Tetsuya Taura4Debapriya Sengupta5Lisa Jo6Angela Sho7Yong Yun8Eric Doan9Anita Jamin10Hussein Hallak11David S. Wilson12Jennifer R. Stratton13Biologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USANon Clinical Development, Teva Pharmaceutical Industries, Netanya, IsraelBiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USABiologics Discovery Science, Teva Pharmaceutical Industries Ltd, Redwood City, CA, USAABSTRACTThe blood-brain barrier (BBB) largely excludes antibodies from entering the central nervous system, thus limiting the potential of therapeutic antibodies to treat conditions such as neurodegenerative diseases and neuro-psychiatric disorders. Here, we demonstrate that the transport of human antibodies across the BBB in mice can be enhanced by modulating their interactions with the neonatal Fc receptor (FcRn). When M252Y/S254T/T246E substitutions are introduced on the antibody Fc domain, immunohistochemical assays reveal widespread distribution of the engineered antibodies throughout the mouse brain. These engineered antibodies remain specific for their antigens and retain pharmacological activity. We propose that novel brain-targeted therapeutic antibodies can be engineered to differentially engage FcRn for receptor-mediated transcytosis across the BBB in order to improve neurological disease therapeutics in the future.https://www.tandfonline.com/doi/10.1080/19420862.2023.2229098Blood-brain barrier (BBB)central nervous system (CNS)immunoglobulin G (IgG)neonatal fc receptor (FcRn)transcytosisTrojan horse |
| spellingShingle | Jason Tien Dmitri Leonoudakis Ralitsa Petrova Vivian Trinh Tetsuya Taura Debapriya Sengupta Lisa Jo Angela Sho Yong Yun Eric Doan Anita Jamin Hussein Hallak David S. Wilson Jennifer R. Stratton Modifying antibody-FcRn interactions to increase the transport of antibodies through the blood-brain barrier mAbs Blood-brain barrier (BBB) central nervous system (CNS) immunoglobulin G (IgG) neonatal fc receptor (FcRn) transcytosis Trojan horse |
| title | Modifying antibody-FcRn interactions to increase the transport of antibodies through the blood-brain barrier |
| title_full | Modifying antibody-FcRn interactions to increase the transport of antibodies through the blood-brain barrier |
| title_fullStr | Modifying antibody-FcRn interactions to increase the transport of antibodies through the blood-brain barrier |
| title_full_unstemmed | Modifying antibody-FcRn interactions to increase the transport of antibodies through the blood-brain barrier |
| title_short | Modifying antibody-FcRn interactions to increase the transport of antibodies through the blood-brain barrier |
| title_sort | modifying antibody fcrn interactions to increase the transport of antibodies through the blood brain barrier |
| topic | Blood-brain barrier (BBB) central nervous system (CNS) immunoglobulin G (IgG) neonatal fc receptor (FcRn) transcytosis Trojan horse |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2229098 |
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