6CT7

Fab of anti-a-synuclein antibody BIIB054 in complex with acetylated a-synuclein peptide (1-10)

Summary for 6CT7

• Entry DOI: 10.2210/pdb6ct7/pdb
• Descriptor: BIIB054 Fab light chain, BIIB054 Fab heavy chain, ACE-MET-ASP-VAL-PHE-MET-LYS-GLY-LEU-SER-LYS, ... (5 entities in total)
• Functional Keywords: fab, complex, a-synuclein, parkinson disease, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 95024.07

Authors

Arndt, J.W. (deposition date: 2018-03-22, release date: 2018-12-19, Last modification date: 2024-10-16)

Primary citation

Weihofen, A.,Liu, Y.,Arndt, J.W.,Huy, C.,Quan, C.,Smith, B.A.,Baeriswyl, J.L.,Cavegn, N.,Senn, L.,Su, L.,Marsh, G.,Auluck, P.K.,Montrasio, F.,Nitsch, R.M.,Hirst, W.D.,Cedarbaum, J.M.,Pepinsky, R.B.,Grimm, J.,Weinreb, P.H.
Development of an aggregate-selective, human-derived alpha-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models.
Neurobiol. Dis., 124:276-288, 2018

PubMed Abstract: Aggregation of α-synuclein (α-syn) is neuropathologically and genetically linked to Parkinson's disease (PD). Since stereotypic cell-to-cell spreading of α-syn pathology is believed to contribute to disease progression, immunotherapy with antibodies directed against α-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 α-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 α-syn residues 1-10. BIIB054 is highly selective for aggregated forms of α-syn with at least an 800-fold higher apparent affinity for fibrillar versus monomeric recombinant α-syn and a strong preference for human PD brain tissue. BIIB054 discriminates between monomers and oligomeric/fibrillar forms of α-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 α-syn fibrils, BIIB054 treatment attenuated the spreading of α-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.

PubMed: 30381260
DOI: 10.1016/j.nbd.2018.10.016

Experimental method

X-RAY DIFFRACTION (1.903 Å)