| 1. |
- Lindström, Veronica, et al.
(författare)
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Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice
- 2014
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 69, s. 134-143
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Tidskriftsartikel (refereegranskat)abstract
- Several lines of evidence suggest that accumulation of aggregated alpha-synuclein (α-synuclein) in the central nervous system (CNS) is an early pathogenic event and therefore a suitable therapeutic target in Parkinson’s disease and other Lewy body disorders. In recent years, animal studies have indicated immunotherapy with antibodies directed against α-synuclein as a promising novel treatment strategy. Since large α-synuclein oligomers, or protofibrils, have been demonstrated to possess pronounced cytotoxic properties, such species should be particularly attractive as therapeutic targets. An α-synuclein protofibril-selective monoclonal antibody, mAb47, was evaluated in the (Thy-1)-h[A30P] α-synuclein transgenic mouse model, featuring an age- and motor dysfunction-associated increase of α-synuclein protofibrils in the CNS. As measured by ELISA, mAb47-treated mice displayed significantly lower levels of both soluble and membrane-associated protofibrils in the spinal cord. In addition, a trend for increased survival as a result of reduced motor symptoms was observed with antibody treatment. Taken together, this study demonstrates reduced levels of pathogenic α-synuclein and indicates a reduction of motor dysfunction in transgenic mice upon peripheral administration of an α-synuclein protofibril-selective antibody. Thus, immunotherapy with antibodies targeting toxic α-synuclein species holds promise as a future disease-modifying treatment in Parkinson’s disease and related disorders.
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| 2. |
- Lord, Anna, et al.
(författare)
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An amyloid-beta protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease
- 2009
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 36:3, s. 425-434
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Tidskriftsartikel (refereegranskat)abstract
- Human genetics link Alzheimer's disease pathogenesis to excessive accumulation of amyloid-beta (Abeta) in brain, but the symptoms do not correlate with senile plaque burden. Since soluble Abeta aggregates can cause synaptic dysfunctions and memory deficits, these species could contribute to neuronal dysfunction and dementia. Here we explored selective targeting of large soluble aggregates, Abeta protofibrils, as a new immunotherapeutic strategy. The highly protofibril-selective monoclonal antibody mAb158 inhibited in vitro fibril formation and protected cells from Abeta protofibril-induced toxicity. When the mAb158 antibody was administered for 4 months to plaque-bearing transgenic mice with both the Arctic and Swedish mutations (tg-ArcSwe), Abeta protofibril levels were lowered while measures of insoluble Abeta were unaffected. In contrast, when treatment began before the appearance of senile plaques, amyloid deposition was prevented and Abeta protofibril levels diminished. Therapeutic intervention with mAb158 was however not proven functionally beneficial, since place learning depended neither on treatment nor transgenicity. Our findings suggest that Abeta protofibrils can be selectively cleared with immunotherapy in an animal model that display highly insoluble Abeta deposits, similar to those of Alzheimer's disease brain.
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| 3. |
- Nordström, Eva, et al.
(författare)
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ABBV-0805, a novel antibody selective for soluble aggregated alpha-synuclein, prolongs lifespan and prevents buildup of alpha-synuclein pathology in mouse models of Parkinson's disease
- 2021
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Ingår i: Neurobiology of Disease. - : Elsevier. - 0969-9961 .- 1095-953X. ; 161
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Tidskriftsartikel (refereegranskat)abstract
- A growing body of evidence suggests that aggregated alpha-synuclein, the major constituent of Lewy bodies, plays a key role in the pathogenesis of Parkinson's disease and related alpha-synucleinopathies. Immunotherapies, both active and passive, against alpha-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 alpha-synuclein and very low affinity for monomers. ABBV-0805 binds to a broad spectrum of soluble aggregated alpha-synuclein, including small and large aggregates of different conformations. Binding of ABBV-0805 to pathological alpha-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 Fc gamma-receptor mediated uptake of soluble aggregated alpha-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 alpha-synuclein aggregates in brain in several mouse models, both in prophylactic and therapeutic settings. In addition, mAb47 treatment of alpha-synuclein transgenic mice resulted in a significantly prolonged survival. ABBV-0805 selectively targets soluble toxic alpha-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.
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