A brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies
Sungwon An, John J. McInnis, Dongin Kim, Yihang Li, Ozge E. Tasdemir-Yilmaz, Jin-Hyung Ahn, Brian C. Mackness, Seung‐Hwan Kwon, Julia Maeve Bonner, Miran Yoo, Simon Dujardin, Donghwan Kim, Jin‐Young 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 Kim, Hyeran Lee, Jinwon Jung, Weon‐Kyoo You, Alexandra T. Star, Christie E. Delaney, Danica Stanimirovic, S. Pablo Sardi, Sang Hoon Lee, Can Kayatekin
Abstract
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.