biostudies-literatureAn SNIA NIH HHS254https://www.ebi.ac.uk/biostudies/studies/S-EPMC12373799biostudies-literatureUnknown11(1)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.NPJ Parkinson's diseaseA brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies.PMC12373799P30 AG066530Kim DStar ATShin JWYun HLee HMackness BCDujardin SStanimirovic DBDelaney CESandhu JKHyeon SRissman RASung BPradier LTang YAn SMcInnis JJSardi SPBonner JMPark JJung JYou WKKayatekin CLee SHSong DSpencer BKrishnan RHaqqani ASLi YTasdemir-Yilmaz OAhn JKwon SHKim DBYoo MfalseA brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies.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.2025-01-01T00:00:00Z2025 Aug2026-06-30T03:23:45.077Z2026-06-30T03:16:24.658ZS-EPMC123737994084702610.1038/s41531-025-01117-6