Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models
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 promis...
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doaj-9c312d730f4444538aa0bb5f11e8cda52021-03-22T12:47:11ZengElsevierNeurobiology of Disease1095-953X2019-04-01124276288Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease modelsAndreas Weihofen0YuTing Liu1Joseph W. Arndt2Christian Huy3Chao Quan4Benjamin A. Smith5Jean-Luc Baeriswyl6Nicole Cavegn7Luzia Senn8Lihe Su9Galina Marsh10Pavan K. Auluck11Fabio Montrasio12Roger M. Nitsch13Warren D. Hirst14Jesse M. Cedarbaum15R. Blake Pepinsky16Jan Grimm17Paul H. Weinreb18Biogen, 225 Binney Street, Cambridge, MA 02142, USA; Neurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland; Corresponding authors at: Biogen, 225 Binney Street, Cambridge, MA 02142, USA.Biogen, 225 Binney Street, Cambridge, MA 02142, USABiogen, 225 Binney Street, Cambridge, MA 02142, USANeurimmune AG, Wagistrasse 13, 8952 Schlieren, SwitzerlandBiogen, 225 Binney Street, Cambridge, MA 02142, USABiogen, 225 Binney Street, Cambridge, MA 02142, USANeurimmune AG, Wagistrasse 13, 8952 Schlieren, SwitzerlandNeurimmune AG, Wagistrasse 13, 8952 Schlieren, SwitzerlandNeurimmune AG, Wagistrasse 13, 8952 Schlieren, SwitzerlandBiogen, 225 Binney Street, Cambridge, MA 02142, USABiogen, 225 Binney Street, Cambridge, MA 02142, USABiogen, 225 Binney Street, Cambridge, MA 02142, USANeurimmune AG, Wagistrasse 13, 8952 Schlieren, SwitzerlandNeurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland; Institute for Regenerative Medicine, University of Zurich, Wagistrasse 12, 8952 Schlieren, SwitzerlandBiogen, 225 Binney Street, Cambridge, MA 02142, USABiogen, 225 Binney Street, Cambridge, MA 02142, USABiogen, 225 Binney Street, Cambridge, MA 02142, USANeurimmune AG, Wagistrasse 13, 8952 Schlieren, SwitzerlandBiogen, 225 Binney Street, Cambridge, MA 02142, USA; Corresponding authors at: Biogen, 225 Binney Street, Cambridge, MA 02142, USA.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.http://www.sciencedirect.com/science/article/pii/S0969996118304480Alpha-synucleinParkinson's diseaseLewy BodiesImmunotherapyBIIB054 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andreas Weihofen YuTing Liu Joseph W. Arndt Christian Huy Chao Quan Benjamin A. Smith Jean-Luc Baeriswyl Nicole Cavegn Luzia Senn Lihe Su Galina Marsh Pavan K. Auluck Fabio Montrasio Roger M. Nitsch Warren D. Hirst Jesse M. Cedarbaum R. Blake Pepinsky Jan Grimm Paul H. Weinreb |
spellingShingle |
Andreas Weihofen YuTing Liu Joseph W. Arndt Christian Huy Chao Quan Benjamin A. Smith Jean-Luc Baeriswyl Nicole Cavegn Luzia Senn Lihe Su Galina Marsh Pavan K. Auluck Fabio Montrasio Roger M. Nitsch Warren D. Hirst Jesse M. Cedarbaum R. Blake Pepinsky Jan Grimm Paul H. Weinreb Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models Neurobiology of Disease Alpha-synuclein Parkinson's disease Lewy Bodies Immunotherapy BIIB054 |
author_facet |
Andreas Weihofen YuTing Liu Joseph W. Arndt Christian Huy Chao Quan Benjamin A. Smith Jean-Luc Baeriswyl Nicole Cavegn Luzia Senn Lihe Su Galina Marsh Pavan K. Auluck Fabio Montrasio Roger M. Nitsch Warren D. Hirst Jesse M. Cedarbaum R. Blake Pepinsky Jan Grimm Paul H. Weinreb |
author_sort |
Andreas Weihofen |
title |
Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models |
title_short |
Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models |
title_full |
Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models |
title_fullStr |
Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models |
title_full_unstemmed |
Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models |
title_sort |
development of an aggregate-selective, human-derived α-synuclein antibody biib054 that ameliorates disease phenotypes in parkinson's disease models |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2019-04-01 |
description |
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. |
topic |
Alpha-synuclein Parkinson's disease Lewy Bodies Immunotherapy BIIB054 |
url |
http://www.sciencedirect.com/science/article/pii/S0969996118304480 |
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