期刊
PHARMACEUTICS
卷 14, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics14071412
关键词
bispecific antibody; blood-brain barrier (BBB); alpha-synuclein (alpha SYN); Parkinson's disease (PD); immunotherapy; monoclonal antibody; transferrin receptor (TfR); receptor-mediated transcytosis (RMT)
资金
- Swedish Research Council [2017-02413, 2018-02715, 2021-03524, 2021-01083]
- Swedish Innovation Agency [2016-04050, 2019-00106]
- Hjarnfonden
- Torsten Soderbergs stiftelse
- Ake Wibergs stiftelse
- Hedlunds stiftelse
- Ahlenstiftelsen
- Parkinsonfonden
- Magnus Bergvalls stiftelse
- Stiftelsen for gamla tjanarinnor
- Stohnes stiftelse
- Neurofonden
- Demensfonden
- Konung Gustaf V:s och Drottning Victorias frimuarestiftelse
- Syskonen Inger och Sixten Norheds stiftelse
- Vinnova [2019-00106, 2016-04050] Funding Source: Vinnova
- Swedish Research Council [2021-03524, 2021-01083] Funding Source: Swedish Research Council
This study investigated a modified bispecific antibody for improved brain uptake in the treatment of Parkinson's disease. The results showed that the antibody could efficiently and quickly penetrate the brain and reduce the aggregation of alpha SYN.
Immunotherapy targeting aggregated alpha-synuclein (alpha SYN) 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 alpha SYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat alpha SYN 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 alpha SYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated alpha SYN 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 alpha SYN antibodies can improve treatment of alpha SYN pathology.
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