دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models.
المؤلفون: Weihofen A; Biogen, 225 Binney Street, Cambridge, MA 02142, USA; Neurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland. Electronic address: andreas.weihofen@biogen.com., Liu Y; Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Arndt JW; Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Huy C; Neurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland., Quan C; Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Smith BA; Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Baeriswyl JL; Neurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland., Cavegn N; Neurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland., Senn L; Neurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland., Su L; Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Marsh G; Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Auluck PK; Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Montrasio F; Neurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland., Nitsch RM; Neurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland; Institute for Regenerative Medicine, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland., Hirst WD; Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Cedarbaum JM; Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Pepinsky RB; Biogen, 225 Binney Street, Cambridge, MA 02142, USA., Grimm J; Neurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland., Weinreb PH; Biogen, 225 Binney Street, Cambridge, MA 02142, USA. Electronic address: paul.weinreb@biogen.com.
المصدر: Neurobiology of disease [Neurobiol Dis] 2019 Apr; Vol. 124, pp. 276-288. Date of Electronic Publication: 2018 Oct 28.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Academic Press Country of Publication: United States NLM ID: 9500169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-953X (Electronic) Linking ISSN: 09699961 NLM ISO Abbreviation: Neurobiol Dis Subsets: MEDLINE
أسماء مطبوعة: Publication: San Diego, CA : Academic Press
Original Publication: Oxford : Blackwell Science, c1994-
مواضيع طبية MeSH: Antibodies, Monoclonal/*pharmacology , Parkinsonian Disorders/*immunology , Parkinsonian Disorders/*pathology , alpha-Synuclein/*antagonists & inhibitors, Animals ; Humans ; Mice ; Phenotype ; Protein Aggregates
مستخلص: 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.
(Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
فهرسة مساهمة: Keywords: Alpha-synuclein; BIIB054; Immunotherapy; Lewy Bodies; Parkinson's disease
المشرفين على المادة: 0 (Antibodies, Monoclonal)
0 (Protein Aggregates)
0 (SNCA protein, human)
0 (alpha-Synuclein)
تواريخ الأحداث: Date Created: 20181102 Date Completed: 20191129 Latest Revision: 20191129
رمز التحديث: 20240628
DOI: 10.1016/j.nbd.2018.10.016
PMID: 30381260
قاعدة البيانات: MEDLINE
الوصف
تدمد:1095-953X
DOI:10.1016/j.nbd.2018.10.016