| 1. |
- Nordström, Eva, et al.
(author)
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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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In: Neurobiology of Disease. - : Elsevier. - 0969-9961 .- 1095-953X. ; 161
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Journal article (peer-reviewed)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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| 2. |
- Rizoska, Biljana, et al.
(author)
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Disease modifying effects of the amyloid-beta protofibril-selective antibody mAb158 in aged Tg2576 transgenic mice
- 2024
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In: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 130
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Journal article (peer-reviewed)abstract
- Amyloid beta (Aβ) peptides, which aggregate to form neocortical plaques in Alzheimer's disease, exist in states that range from soluble monomers and oligomers/protofibrils to insoluble fibrillar amyloid. The present study evaluated the effects of mAb158, a mouse monoclonal antibody version of lecanemab that preferentially binds to soluble Aβ protofibrils, in aged transgenic mice (Tg2576) with Aβ pathology. Female Tg2576 mice (12 months old) received weekly intraperitoneal mAb158 (35 mg/kg) or vehicle for 4 weeks or for 18 weeks, with or without a subsequent 12-week off-treatment period. Aβ protofibril levels were significantly lower in mAb158-treated animals at both 4 and 18 weeks, while longer treatment duration (18 weeks) was required to observe significantly lower Aβ42 levels in insoluble brain fractions and lower Aβ plaque load. Following the off-treatment period, comparison of the vehicle- and mAb158-treated mice demonstrated that the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load remained significantly lower in mAb158-treated animals, as compared with age-matched controls. However, there was a significant increase of brain accumulation of both the Aβ protofibril levels, insoluble Aβ42 levels and Aβ plaque load after treatment cessation. Thus, repeated mAb158 treatment of aged Tg2576 mice first reduced Aβ protofibril levels within 4 weeks of treatment, which then was followed by a reduction of amyloid plaque pathology within 18 weeks of treatment. These effects were maintained 12 weeks after the final dose, indicating that mAb158 had a disease-modifying effect on the Aβ pathology in this mouse model. In addition, brain accumulation of both Aβ protofibril levels and amyloid pathology progressed after discontinuation of the treatment which supports the importance of continued treatment with mAb158 to maintain the effects on Aβ pathology.
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| 3. |
- Yngve, Ulrika, et al.
(author)
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Triazolopyrimidinones as gamma-secretase modulators : structure-activity relationship, modulator profile, and in vivo profiling
- 2013
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In: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:2, s. 422-431
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Journal article (peer-reviewed)abstract
- The structure-activity relationship for a series of potent g-secretase modulators based on the 6,7-dihydro4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one scaffold is described. Furthermore, we report details regarding the modulator profile on A beta processing, as well as in vivo efficacy, for the optimized compounds.
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