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Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody

Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson’s disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the...

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Autores principales: Roshanbin, Sahar, Julku, Ulrika, Xiong, Mengfei, Eriksson, Jonas, Masliah, Eliezer, Hultqvist, Greta, Bergström, Joakim, Ingelsson, Martin, Syvänen, Stina, Sehlin, Dag
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318263/
https://www.ncbi.nlm.nih.gov/pubmed/35890306
http://dx.doi.org/10.3390/pharmaceutics14071412
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author Roshanbin, Sahar
Julku, Ulrika
Xiong, Mengfei
Eriksson, Jonas
Masliah, Eliezer
Hultqvist, Greta
Bergström, Joakim
Ingelsson, Martin
Syvänen, Stina
Sehlin, Dag
author_facet Roshanbin, Sahar
Julku, Ulrika
Xiong, Mengfei
Eriksson, Jonas
Masliah, Eliezer
Hultqvist, Greta
Bergström, Joakim
Ingelsson, Martin
Syvänen, Stina
Sehlin, Dag
author_sort Roshanbin, Sahar
collection PubMed
description Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson’s disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat αSYN pathology in transgenic mice. Ex vivo analyses of the blood and brain distribution of RmAbSynO2-scFv8D3 and the unmodified variant RmAbSynO2, as well as in vivo analyses with microdialysis and PET, confirmed fast and efficient brain uptake of the bispecific format. In addition, intravenous administration was shown to be superior to intraperitoneal injections in terms of brain uptake and distribution. Next, aged female αSYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated αSYN in the brain following treatment with RmAbSynO2-scFv8D3 were decreased in the cortex and midbrain compared to RmAbSynO2 or PBS controls. Taken together, our results indicate that facilitated brain uptake of αSYN antibodies can improve treatment of αSYN pathology.
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spelling pubmed-93182632022-07-27 Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody Roshanbin, Sahar Julku, Ulrika Xiong, Mengfei Eriksson, Jonas Masliah, Eliezer Hultqvist, Greta Bergström, Joakim Ingelsson, Martin Syvänen, Stina Sehlin, Dag Pharmaceutics Article Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson’s disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat αSYN pathology in transgenic mice. Ex vivo analyses of the blood and brain distribution of RmAbSynO2-scFv8D3 and the unmodified variant RmAbSynO2, as well as in vivo analyses with microdialysis and PET, confirmed fast and efficient brain uptake of the bispecific format. In addition, intravenous administration was shown to be superior to intraperitoneal injections in terms of brain uptake and distribution. Next, aged female αSYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated αSYN in the brain following treatment with RmAbSynO2-scFv8D3 were decreased in the cortex and midbrain compared to RmAbSynO2 or PBS controls. Taken together, our results indicate that facilitated brain uptake of αSYN antibodies can improve treatment of αSYN pathology. MDPI 2022-07-05 /pmc/articles/PMC9318263/ /pubmed/35890306 http://dx.doi.org/10.3390/pharmaceutics14071412 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Roshanbin, Sahar
Julku, Ulrika
Xiong, Mengfei
Eriksson, Jonas
Masliah, Eliezer
Hultqvist, Greta
Bergström, Joakim
Ingelsson, Martin
Syvänen, Stina
Sehlin, Dag
Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody
title Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody
title_full Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody
title_fullStr Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody
title_full_unstemmed Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody
title_short Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody
title_sort reduction of αsyn pathology in a mouse model of pd using a brain-penetrating bispecific antibody
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318263/
https://www.ncbi.nlm.nih.gov/pubmed/35890306
http://dx.doi.org/10.3390/pharmaceutics14071412
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