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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月22日

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  • Sungwon An,
  • John J. McInnis,
  • Dongin Kim,
  • Yihang Li,
  • Ozge Tasdemir-Yilmaz,
  • Jinhyung Ahn,
  • Brian C. Mackness,
  • Seung-Hwan Kwon,
  • Julia Maeve Bonner,
  • Miran Yoo,
  • Simon Dujardin,
  • Donghwan Kim,
  • Jinyoung Park,
  • Hyesu Yun,
  • Yi Tang,
  • Laurent Pradier,
  • Sumin Hyeon,
  • Daehae Song,
  • Byungje Sung,
  • Rajaraman Krishnan,
  • Brian Spencer,
  • Robert A. Rissman,
  • Jagdeep K. Sandhu,
  • Arsalan S. Haqqani,
  • Jung-Won Shin,
  • Donghwan B. Kim,
  • Hyeran Lee,
  • Jinwon Jung,
  • Weon-Kyoo You,
  • Alexandra T. Star,
  • Christie E. Delaney,
  • Danica B. Stanimirovic,
  • Sergio Pablo Sardi,
  • Sang Hoon Lee,
  • Can Kayatekin

摘要

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.