First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers

Schenk, Dale; Koller, Martin; Ness, Daniel; Griffith, Sue G.; Grundman, Michael; Zago, Wagner; Soto, Jay; Atiee, George; Ostrowitzki, Susanne; Kinney, Gene G.

doi:10.1002/mds.26878

Cited by 223 publications

(176 citation statements)

References 37 publications

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“…At present, two main antibodies targeting α‐syn have been tested in clinical trials: BIIB054 and PRX002 . The first one is an aggregate‐selective human‐α‐syn‐derived antibody, which could ameliorate disease phenotype in mouse models of synucleinopathy .…”

Section: The Possible Approaches To Directly Target α‐Syn Pathologymentioning

confidence: 99%

“…It has been found that BIIB054 possesses favorable safety, tolerability, and pharmacokinetic profiles in volunteers and moderate PD (Hoehn and Yahr stage ≤2.5, and time since PD diagnosis ≤5 years) patients . The second, PRX002, is derived from the murine monoclonal antibody 9E4 and preferentially targets soluble and insoluble aggregated forms of α‐syn . In a first Phase 1 study, it showed efficient serum α‐syn binding ability as well as favorable safety, tolerability, and pharmacokinetic profiles at all doses tested, with no immunogenicity .…”

Section: The Possible Approaches To Directly Target α‐Syn Pathologymentioning

confidence: 99%

“…The second, PRX002, is derived from the murine monoclonal antibody 9E4 and preferentially targets soluble and insoluble aggregated forms of α‐syn . In a first Phase 1 study, it showed efficient serum α‐syn binding ability as well as favorable safety, tolerability, and pharmacokinetic profiles at all doses tested, with no immunogenicity . In a following multicenter, randomized, double‐blind, placebo‐controlled trial, assessing multiple ascending doses of PRX002 in mild‐to‐moderate idiopathic PD patients aged 40 to 80 years (Hoehn and Yahr Stages 1–3), both single and multiple doses of this antibody resulted safe, were well tolerated, and produced robust binding of peripheral α‐syn as well as dose‐dependent increases of PRX002 in cerebrospinal fluid .…”

Section: The Possible Approaches To Directly Target α‐Syn Pathologymentioning

confidence: 99%

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The good and bad of therapeutic strategies that directly target α‐synuclein

et al. 2019

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Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α‐synuclein (α‐syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α‐syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α‐syn pathology. This poses the question of which is the most toxic α‐syn species. What is worst, α‐syn appears as a very peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α‐helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α‐syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or overexpression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α‐syn levels, oligomer formation, fibrillation, or cell‐to‐cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α‐syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state‐of‐the‐art α‐syn biology.

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Section: The Possible Approaches To Directly Target α‐Syn Pathologymentioning

confidence: 99%

Section: The Possible Approaches To Directly Target α‐Syn Pathologymentioning

confidence: 99%

Section: The Possible Approaches To Directly Target α‐Syn Pathologymentioning

confidence: 99%

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The good and bad of therapeutic strategies that directly target α‐synuclein

et al. 2019

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“…Early imaging of α-syn load will be important in disease-modifying LBD and MSA therapeutic trials. Anti-synuclein clinical trials are currently underway and are aimed at slowing down or reversing neurodegenerative damage caused by oligomeric or fibrillar α-syn species (240, 241). As the AD therapy community has learned, it will be important to accurately diagnose and identify α-syn patients for early treatment.…”

Section: α-Synucleinopathiesmentioning

confidence: 99%

Small-molecule PET Tracers for Imaging Proteinopathies

Mathis

Lopresti

Ikonomović

et al. 2017

Seminars in Nuclear Medicine

103

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In this chapter, we provide a review of the challenges and advances in developing successful positron emission tomography (PET) imaging agents for three major types of aggregated amyloid proteins – amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn). These three amyloids are involved in the pathogenesis of a variety of neurodegenerative diseases, referred to as proteinopathies or proteopathies, that include Alzheimer’s disease, Lewy body dementias, multiple system atrophy, and frontal temporal dementias among others. In the Introduction, we briefly discuss the history of amyloid in neurodegenerative diseases and describe why progress in developing effective imaging agents has been hampered by the failure of crystallography to provide definitive ligand-protein interactions for rational radioligand design efforts. Instead, the field has relied on largely serendipitous, trial and error methods to achieve useful and specific PET amyloid imaging tracers for Aβ, tau, and α-syn deposits. Because many of the proteopathies involve more than one amyloid protein, it is important to develop selective PET tracers for the different amyloids to help assess the relative contribution of each to total amyloid burden. We utilize Pittsburgh Compound B (PiB) to illustrate some of the critical steps in developing a potent and selective Aβ PET imaging agent. Other selective Aβ and tau PET imaging compounds have followed similar pathways in their developmental processes. Success for selective α-syn PET imaging agents has not been realized yet, but work is ongoing in multiple laboratories throughout the world. In the tau sections, we provide background regarding 3-repeat (3R) and 4-repeat (4R) tau proteins and how they can affect the binding of tau radioligands in different tauopathies. We review the ongoing efforts to assess the properties of tau ligands, which are useful in 3R, 4R or combined 3R/4R tauopathies. Finally, we describe in the α-syn sections recent attempts to develop selective tracers to image α-synucleinopathies.

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“…An α-syn passive immunotherapy approach using a humanized monoclonal antibody against α-syn (Prothena, PRX002) has also been tested in Phase Ia and Ib clinical trials. In both trials, free serum α-syn levels were drastically reduced (Schenk et al, 2017). A dose-dependent increase in PRX002 levels in cerebrospinal fluid was observed, without serious adverse events.…”

Section: Therapeutic Opportunities Based On the Msa Neuropathologymentioning

confidence: 99%

The neuropathology of multiple system atrophy and its therapeutic implications

Valera

Masliah

2018

Autonomic Neuroscience

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Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the abnormal accumulation of toxic forms of the synaptic protein alpha-synuclein (α-syn) within oligodendrocytes and neurons. The presence of α-syn within oligodendrocytes in the form of glial cytoplasmic inclusions is the diagnostic hallmark of MSA. However, it has been postulated that α-syn is produced in neurons and propagates to oligodendrocytes, where unknown mechanisms lead to its accumulation. The presence of α-syn within neurons in MSA has not been so extensively studied, but it may shed light into neuropathological mechanisms leading to oligodendroglial accumulation. Here we summarize the principal neuropathological events of MSA, and discuss how a deeper knowledge of these mechanisms may help develop effective therapies targeting α-syn accumulation and spreading.

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First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers

Cited by 223 publications

References 37 publications

The good and bad of therapeutic strategies that directly target α‐synuclein

The good and bad of therapeutic strategies that directly target α‐synuclein

Small-molecule PET Tracers for Imaging Proteinopathies

The neuropathology of multiple system atrophy and its therapeutic implications

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