6ct7 | pdb_00006ct7
Fab of anti-a-synuclein antibody BIIB054 in complex with acetylated a-synuclein peptide (1-10)
Structural highlights
Publication Abstract from PubMedAggregation 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. Development of an aggregate-selective, human-derived alpha-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models.,Weihofen A, Liu Y, Arndt JW, Huy C, Quan C, Smith BA, Baeriswyl JL, Cavegn N, Senn L, Su L, Marsh G, Auluck PK, Montrasio F, Nitsch RM, Hirst WD, Cedarbaum JM, Pepinsky RB, Grimm J, Weinreb PH Neurobiol Dis. 2018 Oct 28;124:276-288. doi: 10.1016/j.nbd.2018.10.016. PMID:30381260[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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