ABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease

A growing body of evidence suggests that aggregated α-synuclein, the major constituent of Lewy bodies, plays a key role in the pathogenesis of Parkinson's disease and related α-synucleinopathies. Immunotherapies, both active and passive, against α-synuclein have been developed and are promising...

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Autores principales:	Eva Nordström, Fredrik Eriksson, Jessica Sigvardson, Malin Johannesson, Alex Kasrayan, Martina Jones-Kostalla, Paulina Appelkvist, Linda Söderberg, Patrik Nygren, Magdalena Blom, Adeline Rachalski, Karin Nordenankar, Olof Zachrisson, Ebba Amandius, Gunilla Osswald, Mikael Moge, Martin Ingelsson, Joakim Bergström, Lars Lannfelt, Christer Möller, Marco Giorgetti, Johanna Fälting
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Parkinson's disease α-Synuclein Humanized monoclonal antibody Immunotherapy Clinical development ABBV-0805 Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/707d9ab628d84f509f885d36c2242dcb
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spelling	oai:doaj.org-article:707d9ab628d84f509f885d36c2242dcb2021-12-04T04:33:10ZABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease1095-953X10.1016/j.nbd.2021.105543https://doaj.org/article/707d9ab628d84f509f885d36c2242dcb2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0969996121002928https://doaj.org/toc/1095-953XA growing body of evidence suggests that aggregated α-synuclein, the major constituent of Lewy bodies, plays a key role in the pathogenesis of Parkinson's disease and related α-synucleinopathies. Immunotherapies, both active and passive, against α-synuclein have been developed and are promising novel treatment strategies for such disorders. Here, we report on the humanization and pharmacological characteristics of ABBV-0805, a monoclonal antibody that exhibits a high selectivity for human aggregated α-synuclein and very low affinity for monomers. ABBV-0805 binds to a broad spectrum of soluble aggregated α-synuclein, including small and large aggregates of different conformations.Binding of ABBV-0805 to pathological α-synuclein was demonstrated in Lewy body-positive post mortem brains of Parkinson's disease patients. The functional potency of ABBV-0805 was demonstrated in several cellular assays, including Fcγ-receptor mediated uptake of soluble aggregated α-synuclein in microglia and inhibition of neurotoxicity in primary neurons. In vivo, the murine version of ABBV-0805 (mAb47) displayed significant dose-dependent decrease of α-synuclein aggregates in brain in several mouse models, both in prophylactic and therapeutic settings. In addition, mAb47 treatment of α-synuclein transgenic mice resulted in a significantly prolonged survival.ABBV-0805 selectively targets soluble toxic α-synuclein aggregates with a picomolar affinity and demonstrates excellent in vivo efficacy. Based on the strong preclinical findings described herein, ABBV-0805 has been progressed into clinical development as a potential disease-modifying treatment for Parkinson's disease.Eva NordströmFredrik ErikssonJessica SigvardsonMalin JohannessonAlex KasrayanMartina Jones-KostallaPaulina AppelkvistLinda SöderbergPatrik NygrenMagdalena BlomAdeline RachalskiKarin NordenankarOlof ZachrissonEbba AmandiusGunilla OsswaldMikael MogeMartin IngelssonJoakim BergströmLars LannfeltChrister MöllerMarco GiorgettiJohanna FältingElsevierarticleParkinson's diseaseα-SynucleinHumanized monoclonal antibodyImmunotherapyClinical developmentABBV-0805Neurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENNeurobiology of Disease, Vol 161, Iss , Pp 105543- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Parkinson's disease α-Synuclein Humanized monoclonal antibody Immunotherapy Clinical development ABBV-0805 Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Parkinson's disease α-Synuclein Humanized monoclonal antibody Immunotherapy Clinical development ABBV-0805 Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Eva Nordström Fredrik Eriksson Jessica Sigvardson Malin Johannesson Alex Kasrayan Martina Jones-Kostalla Paulina Appelkvist Linda Söderberg Patrik Nygren Magdalena Blom Adeline Rachalski Karin Nordenankar Olof Zachrisson Ebba Amandius Gunilla Osswald Mikael Moge Martin Ingelsson Joakim Bergström Lars Lannfelt Christer Möller Marco Giorgetti Johanna Fälting ABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease
description	A growing body of evidence suggests that aggregated α-synuclein, the major constituent of Lewy bodies, plays a key role in the pathogenesis of Parkinson's disease and related α-synucleinopathies. Immunotherapies, both active and passive, against α-synuclein have been developed and are promising novel treatment strategies for such disorders. Here, we report on the humanization and pharmacological characteristics of ABBV-0805, a monoclonal antibody that exhibits a high selectivity for human aggregated α-synuclein and very low affinity for monomers. ABBV-0805 binds to a broad spectrum of soluble aggregated α-synuclein, including small and large aggregates of different conformations.Binding of ABBV-0805 to pathological α-synuclein was demonstrated in Lewy body-positive post mortem brains of Parkinson's disease patients. The functional potency of ABBV-0805 was demonstrated in several cellular assays, including Fcγ-receptor mediated uptake of soluble aggregated α-synuclein in microglia and inhibition of neurotoxicity in primary neurons. In vivo, the murine version of ABBV-0805 (mAb47) displayed significant dose-dependent decrease of α-synuclein aggregates in brain in several mouse models, both in prophylactic and therapeutic settings. In addition, mAb47 treatment of α-synuclein transgenic mice resulted in a significantly prolonged survival.ABBV-0805 selectively targets soluble toxic α-synuclein aggregates with a picomolar affinity and demonstrates excellent in vivo efficacy. Based on the strong preclinical findings described herein, ABBV-0805 has been progressed into clinical development as a potential disease-modifying treatment for Parkinson's disease.
format	article
author	Eva Nordström Fredrik Eriksson Jessica Sigvardson Malin Johannesson Alex Kasrayan Martina Jones-Kostalla Paulina Appelkvist Linda Söderberg Patrik Nygren Magdalena Blom Adeline Rachalski Karin Nordenankar Olof Zachrisson Ebba Amandius Gunilla Osswald Mikael Moge Martin Ingelsson Joakim Bergström Lars Lannfelt Christer Möller Marco Giorgetti Johanna Fälting
author_facet	Eva Nordström Fredrik Eriksson Jessica Sigvardson Malin Johannesson Alex Kasrayan Martina Jones-Kostalla Paulina Appelkvist Linda Söderberg Patrik Nygren Magdalena Blom Adeline Rachalski Karin Nordenankar Olof Zachrisson Ebba Amandius Gunilla Osswald Mikael Moge Martin Ingelsson Joakim Bergström Lars Lannfelt Christer Möller Marco Giorgetti Johanna Fälting
author_sort	Eva Nordström
title	ABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease
title_short	ABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease
title_full	ABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease
title_fullStr	ABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease
title_full_unstemmed	ABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease
title_sort	abbv-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of parkinson's disease
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/707d9ab628d84f509f885d36c2242dcb
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ABBV-0805, a novel antibody selective for soluble aggregated α-synuclein, prolongs lifespan and prevents buildup of α-synuclein pathology in mouse models of Parkinson's disease

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