A brain-penetrant bispecific antibody lowers oligomeric alpha-synuclein and activates microglia in a mouse model of alpha-synuclein pathology
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, linked to aggregation of alpha-synuclein (αSYN) into Lewy bodies. Current treatments are symptomatic and do not halt or reverse the neurodegeneration. Immunotherapy targeting aggregated αSYN shows potential...
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Elsevier
2025-03-01
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| Series: | Neurotherapeutics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878747924001971 |
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| author | Dag Sehlin Sahar Roshanbin Olof Zachrisson Martin Ingelsson Stina Syvänen |
| author_facet | Dag Sehlin Sahar Roshanbin Olof Zachrisson Martin Ingelsson Stina Syvänen |
| author_sort | Dag Sehlin |
| collection | DOAJ |
| description | Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, linked to aggregation of alpha-synuclein (αSYN) into Lewy bodies. Current treatments are symptomatic and do not halt or reverse the neurodegeneration. Immunotherapy targeting aggregated αSYN shows potential, but therapeutic efficacy is limited by poor brain penetration of antibodies. We developed a bispecific antibody, RmAb38E2-scFv8D3, based on αSYN oligomer selective RmAb38E2 fused to a transferrin receptor (TfR)-binding domain to enhance brain delivery. Both RmAb38E2 and RmAb38E2-scFv8D3 showed higher affinity for αSYN oligomers than for monomers or fibrils. In vivo, RmAb38E2-scFv8D3 exhibited higher brain and lower blood concentrations compared to RmAb38E2, suggesting a better brain uptake and reduced peripheral exposure for the bispecific antibody. Treatment over five days of 3–4 months old transgenic L61 mice, which overexpress human αSYN, with three doses of RmAb38E2-scFv8D3 reduced brain αSYN oligomer levels and increased microglial activation, as indicated by elevated soluble TREM2 levels. Treatment with the monospecific RmAb38E2, however, showed no significant effect compared to PBS. This study demonstrates that TfR-mediated delivery enhances the therapeutic potential of αSYN-targeted immunotherapy by resulting in a higher concentration and a more uniform distribution of antibodies in the brain. The use of bispecific antibodies offers a promising strategy to improve the efficacy of antibody therapies in PD and other α-synucleinopathies. |
| format | Article |
| id | doaj-art-c6d1c767a92e42e698523899fcae50c1 |
| institution | DOAJ |
| issn | 1878-7479 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurotherapeutics |
| spelling | doaj-art-c6d1c767a92e42e698523899fcae50c12025-08-20T02:55:25ZengElsevierNeurotherapeutics1878-74792025-03-01222e0051010.1016/j.neurot.2024.e00510A brain-penetrant bispecific antibody lowers oligomeric alpha-synuclein and activates microglia in a mouse model of alpha-synuclein pathologyDag Sehlin0Sahar Roshanbin1Olof Zachrisson2Martin Ingelsson3Stina Syvänen4Department of Public Health and Caring Sciences, Uppsala University, 751 85, Uppsala, SwedenDepartment of Public Health and Caring Sciences, Uppsala University, 751 85, Uppsala, SwedenBioArctic AB, Warfvinges väg 35, 112 51, Stockholm, SwedenDepartment of Public Health and Caring Sciences, Uppsala University, 751 85, Uppsala, Sweden; Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada; Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, CanadaDepartment of Public Health and Caring Sciences, Uppsala University, 751 85, Uppsala, Sweden; Corresponding author.Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, linked to aggregation of alpha-synuclein (αSYN) into Lewy bodies. Current treatments are symptomatic and do not halt or reverse the neurodegeneration. Immunotherapy targeting aggregated αSYN shows potential, but therapeutic efficacy is limited by poor brain penetration of antibodies. We developed a bispecific antibody, RmAb38E2-scFv8D3, based on αSYN oligomer selective RmAb38E2 fused to a transferrin receptor (TfR)-binding domain to enhance brain delivery. Both RmAb38E2 and RmAb38E2-scFv8D3 showed higher affinity for αSYN oligomers than for monomers or fibrils. In vivo, RmAb38E2-scFv8D3 exhibited higher brain and lower blood concentrations compared to RmAb38E2, suggesting a better brain uptake and reduced peripheral exposure for the bispecific antibody. Treatment over five days of 3–4 months old transgenic L61 mice, which overexpress human αSYN, with three doses of RmAb38E2-scFv8D3 reduced brain αSYN oligomer levels and increased microglial activation, as indicated by elevated soluble TREM2 levels. Treatment with the monospecific RmAb38E2, however, showed no significant effect compared to PBS. This study demonstrates that TfR-mediated delivery enhances the therapeutic potential of αSYN-targeted immunotherapy by resulting in a higher concentration and a more uniform distribution of antibodies in the brain. The use of bispecific antibodies offers a promising strategy to improve the efficacy of antibody therapies in PD and other α-synucleinopathies.http://www.sciencedirect.com/science/article/pii/S1878747924001971Bispecific antibodyAlpha-synucleinThe blood-brain barrierTransferrin receptor mediated transcytosisParkinson's disease |
| spellingShingle | Dag Sehlin Sahar Roshanbin Olof Zachrisson Martin Ingelsson Stina Syvänen A brain-penetrant bispecific antibody lowers oligomeric alpha-synuclein and activates microglia in a mouse model of alpha-synuclein pathology Neurotherapeutics Bispecific antibody Alpha-synuclein The blood-brain barrier Transferrin receptor mediated transcytosis Parkinson's disease |
| title | A brain-penetrant bispecific antibody lowers oligomeric alpha-synuclein and activates microglia in a mouse model of alpha-synuclein pathology |
| title_full | A brain-penetrant bispecific antibody lowers oligomeric alpha-synuclein and activates microglia in a mouse model of alpha-synuclein pathology |
| title_fullStr | A brain-penetrant bispecific antibody lowers oligomeric alpha-synuclein and activates microglia in a mouse model of alpha-synuclein pathology |
| title_full_unstemmed | A brain-penetrant bispecific antibody lowers oligomeric alpha-synuclein and activates microglia in a mouse model of alpha-synuclein pathology |
| title_short | A brain-penetrant bispecific antibody lowers oligomeric alpha-synuclein and activates microglia in a mouse model of alpha-synuclein pathology |
| title_sort | brain penetrant bispecific antibody lowers oligomeric alpha synuclein and activates microglia in a mouse model of alpha synuclein pathology |
| topic | Bispecific antibody Alpha-synuclein The blood-brain barrier Transferrin receptor mediated transcytosis Parkinson's disease |
| url | http://www.sciencedirect.com/science/article/pii/S1878747924001971 |
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