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
| Autor: | Fredrik Eriksson, Linda Söderberg, Johanna Fälting, Magdalena Blom, Jessica Sigvardson, Karin Nordenankar, Alex Kasrayan, Paulina Appelkvist, Lars Lannfelt, Malin Johannesson, Marco Giorgetti, Ebba Amandius, Eva Nordström, Adeline Rachalski, Olof Zachrisson, Martin Ingelsson, Gunilla Osswald, Martina Jones-Kostalla, Mikael Moge, Patrik Nygren, Christer Möller, Joakim Bergström |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Genetically modified mouse
Parkinson's disease Synucleinopathies medicine.drug_class medicine.medical_treatment mAb47 Longevity Mice Transgenic Neurosciences. Biological psychiatry. Neuropsychiatry Monoclonal antibody Pathogenesis Mice In vivo medicine Animals Humans Humanized monoclonal antibody α-Synuclein Microglia Chemistry Neurotoxicity Neurosciences Antibodies Monoclonal Parkinson Disease Immunotherapy medicine.disease Cell biology nervous system diseases Clinical development medicine.anatomical_structure ABBV-0805 Neurology nervous system alpha-Synuclein Neurovetenskaper RC321-571 |
| Zdroj: | Neurobiology of Disease, Vol 161, Iss, Pp 105543-(2021) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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