Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models

Weihofen, Andreas; Y, Liu; Jw, Arndt; C, Huy; Quan, Chao; Smith, Blair H.; Jl, Baeriswyl; Cavegn, Nicole; Senn, Luzia; L, Su; Marsh, Graham; Pk, Auluck; Montrasio, Fabio; Rm, Nitsch; Hirst, Warren D.; Jm, Cedarbaum; Rb, Pepinsky; Grimm, Jan; Weinreb, Paul H.

doi:10.1016/j.nbd.2018.10.016

Cited by 145 publications

(135 citation statements)

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“…2). In the HVs, the percentage of α‐syn bound to BIIB054 reached 100% at doses ≥15 mg/kg (Supplementary Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

“…The BIIB054/α‐syn complex formation was not assessed in the CSF samples because the BIIB054 CSF concentrations are 250‐fold to 400‐fold lower than in serum, far below the K D for binding of BIIB054 to monomeric α‐syn . No meaningful changes in CSF total α‐syn were observed in the HV and PD participants despite the appearance of numerical increases in α‐syn concentrations at some timepoints (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Monoclonal antibodies that target α‐syn have been shown to reduce α‐syn pathology and ameliorate behavioral deficits in animal models . BIIB054 is a human‐derived monoclonal antibody targeting α‐syn that was generated from a library of memory B cells from elderly individuals with no signs of neurodegenerative disorders . The antibody was engineered with human glycosylated immunoglobulin G1 heavy‐chain and lambda light‐chain constant region sequences and produced in Chinese hamster ovary cells.…”

mentioning

confidence: 99%

“…The antibody was engineered with human glycosylated immunoglobulin G1 heavy‐chain and lambda light‐chain constant region sequences and produced in Chinese hamster ovary cells. BIIB054 has a ≥800‐fold greater apparent affinity for pathologic aggregated α‐syn than for the more abundant physiological monomeric protein . In animal models, BIIB054 treatment attenuated the spreading of α‐syn pathology, rescued motor impairments, and reduced the loss of dopamine transporter density in dopaminergic terminals in striatum, suggesting that BIIB054 has the potential to mitigate α‐syn‐mediated pathological changes and thereby slow the progression of PD.…”

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Randomized phase I clinical trial of anti–α‐synuclein antibody BIIB054

et al. 2019

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Background Pathological and genetic evidence implicates toxic effects of aggregated α‐synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α‐synuclein is a promising strategy for delaying disease progression. Objective This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human‐derived monoclonal antibody that preferentially binds to aggregated α‐synuclein, in healthy volunteers and participants with Parkinson's disease. Methods A total of 48 healthy volunteers (age 40–65, 19 women) and 18 Parkinson's disease participants (age 47–75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single‐dose cohorts of BIIB054 (range 1–135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α‐synuclein complexes were measured in plasma. Results Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half‐life of BIIB054 was 28 to 35 days; the cerebrospinal fluid–to‐serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α‐synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α‐synuclein complex formation. Conclusions BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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“…2). In the HVs, the percentage of α‐syn bound to BIIB054 reached 100% at doses ≥15 mg/kg (Supplementary Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Randomized phase I clinical trial of anti–α‐synuclein antibody BIIB054

et al. 2019

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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 . 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 .…”

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

confidence: 99%

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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The humoral immune landscape in Parkinson's disease: Unraveling antibody and B cell changes

Baridjavadi,

Mahmoudi,

Abdollahi

et al. 2024

Cell Biochemistry & Function

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Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by the accumulation of α‐synuclein (α‐syn) in the brain and progressive loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. Although the role of neuroinflammation and cellular immunity in PD has been extensively studied, the involvement of humoral immunity mediated by antibodies and B cells has received less attention. This article provides a comprehensive review of the current understanding of humoral immunity in PD. Here, we discuss alterations in B cells in PD, including changes in their number and phenotype. Evidence mostly indicates a decrease in the quantity of B cells in PD, accompanied by a shift in the population from naïve to memory cells. Furthermore, the existence of autoantibodies that target several antigens in PD has been investigated (i.e., anti‐α‐syn autoantibodies, anti‐glial‐derived antigen antibodies, anti‐Tau antibodies, antineuromelanin antibodies, and antibodies against the renin‐angiotensin system). Several autoantibodies are generated in PD, which may either provide protection or have harmful effects on disease progression. Furthermore, we have reviewed studies focusing on the utilization of antibodies as a potential treatment for PD, both in animal and clinical trials. This review sheds light on the intricate interplay between antibodies and the pathological processes in PD, including complement system activation.

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Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models

Cited by 145 publications

References 74 publications

Randomized phase I clinical trial of anti–α‐synuclein antibody BIIB054

Randomized phase I clinical trial of anti–α‐synuclein antibody BIIB054

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

The humoral immune landscape in Parkinson's disease: Unraveling antibody and B cell changes

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