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

Nordström, Erik; Eriksson, Fredrik; Sigvardson, Jessica; Johannesson, Malin; Kasrayan, Alex; Jones-Kostalla, Martina; Appelkvist, Paulina; Söderberg, Linda; Nygren, Patrik; Blom, Magdalena; Rachalski, Adeline; Nordenankar, Karin; Zachrisson, Olof; Amandius, Ebba; Osswald, Gunilla; Moge, Mikael; Ingelsson, Martin; Bergström, Joakim; Lannfelt, Lars; Möller, Christer; Giorgetti, Marco; Fälting, Johanna

doi:10.1016/j.nbd.2021.105543

Cited by 30 publications

(28 citation statements)

References 61 publications

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“…The increments of these specific possibly pro-inflammatory nAbs could contribute to the ongoing inflammation, proposed to be initiated by the interplay between the immune system and aSyn [ 43 ]. The rationale behind choosing IgG4 for the ABBV-0805 candidate relies on the hypothesis to reduce inflammation by stabilizing the IgG4 molecule, which lacks the complement-binding functions and has a weaker Fcγ receptor interaction, resulting in less pro-inflammatory responses, which is beneficial for long-term immunization [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

Folke

Bergholt

Pakkenberg

et al. 2022

IJMS

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Multiple-system trophy (MSA) and Parkinson’s Disease (PD) are both progressive, neurodegenerative diseases characterized by neuropathological deposition of aggregated alpha-synuclein (αSyn). The causes behind this aggregation are still unknown. We have reported aberrancies in MSA and PD patients in naturally occurring autoantibodies (nAbs) against αSyn (anti-αSyn-nAbs), which are important partakers in anti-aggregatory processes, immune-mediated clearance, and anti-inflammatory functions. To elaborate further on the timeline of autoimmune aberrancies towards αSyn, we investigated here the Immunoglobulin (Ig) affinity profile and subclass composition (IgG-total, IgG1-4 and IgM) of anti-αSyn-nAbs in serum samples from prodromal (p) phases of MSA and PD. Using an electrochemiluminescence competition immunoassay, we confirmed that the repertoire of high-affinity anti-αSyn-nAbs is significantly reduced in pMSA and pPD. Further, we demonstrated that pPD had increased anti-αSyn IgG-total levels compared to pMSA and controls, concordant with increased anti-αSyn IgG1 levels in pPD. Anti-αSyn IgG2 and IgG4 levels were reduced in pMSA and pPD compared with controls, whereas anti-αSyn IgG3 levels were reduced in pMSA compared to pPD and controls. The results indicate that the impaired reactivity towards αSyn occurs prior to disease onset. The apparent lack of high-affinity anti-αSyn nAbs may result in reduced clearance of αSyn, leading to aggregation of the protein. Thus, this study provides novel insights into possible causes behind the pathogenesis in synucleinopathies such as MSA and PD.

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Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

Folke

Bergholt

Pakkenberg

et al. 2022

IJMS

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“…They suggested an autophagy-directed elimination of αsyn [ 113 ]. Very recently, Nordström and colleagues thoroughly investigated the mAb47 (murine version of ABBV-0805), firstly establishing the binding region of the mAb to the C-terminal (121–127 aa) of αsyn, but more selective for aggregated αsyn species [ 119 ]. Nordström and colleagues extensively evaluated mAb47 in three different PD mice models with and without injection of preformed fibrils (to induce seeding) in both a prophylactic and therapeutic manner.…”

Section: Passive Immunization Strategies In Animal Models and Clinica...mentioning

confidence: 99%

“…Lastly, they investigated the efficacy of mAb47 in an A53T+/− intracerebral fibril-seeding mice model with fibril injection into the anterior olfactory nucleus. After 16 weeks of weekly mAb47 intraperitoneal administration, spreading of phosphorylated αsyn was reduced in the CA1 hippocampal region [ 119 ]. El-Agnaf and colleagues studied three antibodies selective for oligomers and aggregates (Syn-01, Syn-02 and Syn-04) and two for mature aggregates (Syn-F1 and Syn-F2) [ 111 ].…”

Section: Passive Immunization Strategies In Animal Models and Clinica...mentioning

confidence: 99%

Passive Immunization in Alpha-Synuclein Preclinical Animal Models

et al. 2022

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Alpha-synucleinopathies include Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. These are all progressive neurodegenerative diseases that are characterized by pathological misfolding and accumulation of the protein alpha-synuclein (αsyn) in neurons, axons or glial cells in the brain, but also in other organs. The abnormal accumulation and propagation of pathogenic αsyn across the autonomic connectome is associated with progressive loss of neurons in the brain and peripheral organs, resulting in motor and non-motor symptoms. To date, no cure is available for synucleinopathies, and therapy is limited to symptomatic treatment of motor and non-motor symptoms upon diagnosis. Recent advances using passive immunization that target different αsyn structures show great potential to block disease progression in rodent studies of synucleinopathies. However, passive immunotherapy in clinical trials has been proven safe but less effective than in preclinical conditions. Here we review current achievements of passive immunotherapy in animal models of synucleinopathies. Furthermore, we propose new research strategies to increase translational outcome in patient studies, (1) by using antibodies against immature conformations of pathogenic αsyn (monomers, post-translationally modified monomers, oligomers and protofibrils) and (2) by focusing treatment on body-first synucleinopathies where damage in the brain is still limited and effective immunization could potentially stop disease progression by blocking the spread of pathogenic αsyn from peripheral organs to the brain.

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“…Aside from aiding in microglia‐mediated extracellular clearance of α‐syn in vitro and in vivo, treatment with an antibody against the C‐terminus of α‐syn was found to prevent cell‐to‐cell transmission of α‐syn (Bae et al., 2012 ) and to ameliorate motor symptoms (Games et al., 2014 ) in transgenic (tg) mice. Furthermore, in collaboration with BioArctic AB, we developed oligomer/protofibril selective α‐syn antibodies (Fagerqvist et al., 2013 ) and found that treatment with such antibodies can reduce levels of aggregated α‐syn in a cell model (Nasstrom et al., 2011 ) as well as in the central nervous system (CNS) of an SNCA tg mouse model (Lindstrom et al., 2014 ; Nordstrom et al., 2021 ).…”

Section: The Central Role Of α‐Syn Aggregationmentioning

confidence: 99%

Modeling Parkinson's disease‐related symptoms in alpha‐synuclein overexpressing mice

et al. 2022

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Background: Intracellular deposition of alpha-synuclein (α-syn) as Lewy bodies andLewy neurites is a central event in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies. Transgenic mouse models overexpressing human α-syn, are useful research tools in preclinical studies of pathogenetic mechanisms. Such mice develop α-syn inclusions as well as neurodegeneration with a topographical distribution that varies depending on the choice of promoter and which form of α-syn that is overexpressed. Moreover, they display motor symptoms and cognitive disturbances that to some extent resemble the human conditions.Purpose: One of the main motives for assessing behavior in these mouse models is to evaluate the potential of new treatment strategies, including their impact on motor and cognitive symptoms. However, due to a high within-group variability with respect to such features, the behavioral studies need to be applied with caution. In this review, we discuss how to make appropriate choices in the experimental design and which tests that are most suitable for the evaluation of PD-related symptoms in such studies. Methods:We have evaluated published results on two selected transgenic mouse models overexpressing wild type (L61) and mutated (A30P) α-syn in the context of their validity and utility for different types of behavioral studies. Conclusions:By applying appropriate behavioral tests, α-syn transgenic mouse models provide an appropriate experimental platform for studies of symptoms related to PD and other α-synucleinopathies.

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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

Cited by 30 publications

References 61 publications

Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

Passive Immunization in Alpha-Synuclein Preclinical Animal Models

Modeling Parkinson's disease‐related symptoms in alpha‐synuclein overexpressing mice

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