期刊
NEUROBIOLOGY OF DISEASE
卷 124, 期 -, 页码 276-288出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2018.10.016
关键词
Alpha-synudein; Parkinson's disease; Lewy Bodies; Immunotherapy; BIIB054
资金
- U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
Aggregation of alpha-synuclein (alpha-syn) is neuropathologically and genetically linked to Parkinson's disease (PD). Since stereotypic cell-to-cell spreading of alpha-syn pathology is believed to contribute to disease progression, immunotherapy with antibodies directed against alpha-syn is considered a promising therapeutic approach for slowing disease progression. Here we report the identification, binding characteristics, and efficacy in PD mouse models of the human-derived alpha-syn antibody BIIB054, which is currently under investigation in a Phase 2 clinical trial for PD. BIIB054 was generated by screening human memory B-cell libraries from healthy elderly individuals. Epitope mapping studies conducted using peptide scanning, X-ray crystallography, and mutagenesis show that BIIB054 binds to alpha-syn residues 1-10. BIIB054 is highly selective for aggregated forms of alpha-syn with at least an 800-fold higher apparent affinity for fibrillar versus monomeric recombinant alpha-syn and a strong preference for human PD brain tissue. BIIB054 discriminates between monomers and oligomeric/fibrillar forms of alpha-syn based on high avidity for aggregates, driven by weak monovalent affinity and fast binding kinetics. In efficacy studies in three different mouse models with intracerebrally inoculated preformed alpha-syn fibrils, BIIB054 treatment attenuated the spreading of alpha-syn pathology, rescued motor impairments, and reduced the loss of dopamine transporter density in dopaminergic terminals in striatum. The preclinical data reported here provide a compelling rationale for clinical development of BIIB054 for the treatment and prevention of PD.
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