Details

Autor(en) / Beteiligte

• Weihofen, Andreas
• Liu, YuTing
• Arndt, Joseph W.
• Huy, Christian
• Quan, Chao
• Smith, Benjamin A.
• Baeriswyl, Jean-Luc
• Cavegn, Nicole
• Senn, Luzia
• Su, Lihe
• Marsh, Galina
• Auluck, Pavan K.
• Montrasio, Fabio
• Nitsch, Roger M.
• Hirst, Warren D.
• Cedarbaum, Jesse M.
• Pepinsky, R. Blake
• Grimm, Jan
• Weinreb, Paul H.

Titel

Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models

Ist Teil von

• Neurobiology of disease, 2019-04, Vol.124 (C), p.276-288

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. •Identification of an aggregate selective human-derived antibody to α-synuclein.•BIIB054 shows ≥800-fold higher binding to aggregates than monomer.•Structure activity relationship of the BIIB054/α-synuclein complex.•BIIB054 treatment in mice reduces spread of pathology and improves motor function.