A brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies.

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作者:An Sungwon, McInnis John J, Kim Dongin, Li Yihang, Tasdemir-Yilmaz Ozge, Ahn Jinhyung, Mackness Brian C, Kwon Seung-Hwan, Bonner Julia Maeve, Yoo Miran, Dujardin Simon, Kim Donghwan, Park Jinyoung, Yun Hyesu, Tang Yi, Pradier Laurent, Hyeon Sumin, Song Daehae, Sung Byungje, Krishnan Rajaraman, Spencer Brian, Rissman Robert A, Sandhu Jagdeep K, Haqqani Arsalan S, Shin Jung-Won, Kim Donghwan B, Lee Hyeran, Jung Jinwon, You Weon-Kyoo, Star Alexandra T, Delaney Christie E, Stanimirovic Danica B, Sardi Sergio Pablo, Lee Sang Hoon, Kayatekin Can
Parkinson's disease and multiple system atrophy are members of a class of devastating neurodegenerative diseases called synucleinopathies, which are characterized by the presence of alpha-synuclein (α-Syn) rich aggregates in the brains of patients. Passive immunotherapy targeting these aggregates is an attractive disease-modifying strategy, which must not only demonstrate target selectivity towards α-Syn aggregates, but also achieve appropriate brain exposure to have the desired therapeutic effect. Here we present preclinical data for SAR446159, a next-generation antibody for the treatment of synucleinopathies. SAR446159 is a bispecific antibody composed of an α-Syn-binding immunoglobulin and an engineered insulin-like growth factor receptor 1 binding single-chain variable fragment, acting as a shuttle to transport an antibody across the blood-brain barrier. SAR446159 binds tightly and preferentially to α-Syn aggregates and prevents their seeding capacity in vitro and in vivo. The binding properties of SAR446159 combined with its brain-shuttle technology make it a potent immunotherapeutic for treating synucleinopathies.

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