Therapeutically effective antibodies against amyloid-β peptide target amyloid-β residues 4–10 and inhibit cytotoxicity and fibrillogenesis

McLaurin, JoAnne; Cecal, Roxana; Kierstead, Meredith E.; Tian, Xiaodan; Phinney, Amie L.; Manea, Marilena; French, John B.; Lambermon, Mark H. L.; Darabie, Audrey A.; Brown, Mary Elizabeth; Janus, Christopher; Chishti, M. Azhar; Horne, Patrick; Westaway, David; Fraser, Paul E.; Mount, Howard T.J.; Przybylski, Michael; George-Hyslop, Peter St

doi:10.1038/nm790

Cited by 401 publications

(330 citation statements)

References 32 publications

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“…In this sense, the use of antibodies directed against specific epitopes or conformations of Aβ has yielded promising results. Passive immunization approaches using monoclonal antibodies against Aβ1-40 [103], Aβ1-42 [104], pyroglutamate Aβ [105], oligomers [106], or protofibrils [107][108][109] have been developed. Currently, clinical trials with the antibodies BAN2401 (recognizing protofibrils) [75], crenezumab (aggregated species) [76], gantenerumab (fibrils) [78][79][80], and solanezumab (Aβ mid-domain) [81,82] are ongoing (Table 1).…”

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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“…Studies of antibody binding can provide clues for the answers to such questions. Antibodies specific to the N-terminal sequence of Ab-peptide have been found to inhibit in vitro aggregation and stimulate the disassembly of preformed fibrils leading to the inhibition of their cytotoxicity [64][65][66][67].…”

Section: Probes Of Structural Features Of Mature Fibrilsmentioning

confidence: 99%

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Dumoulin

Dobson

2004

Biochimie

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The deposition of proteins in the form of amyloid fibrils is the characteristic feature of more than 20 medical conditions affecting the central nervous system or a variety of peripheral tissues. These disorders, which include Alzheimer's disease, the prion diseases and type II diabetes, are of enormous importance in the context of present-day human health and welfare. Extensive research is therefore being carried out to define the molecular details of the mechanism of the pathological conversion of amyloidogenic proteins from their soluble forms into fibrillar structures. This review focuses on recent studies that demonstrate the power of using antibodies or antibody fragments to probe the process of fibril formation, and discusses the emerging potential of these species as diagnostic and therapeutic agents.

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“…40 As indicated, a range of immune-based interventions, including vaccination with the Ab peptide, 41 and passive delivery of antibodies against Ab have all been demonstrated to be effective, to some extent, in APP/PS1 Tg mouse models of AD, in terms of decreasing Ab deposition and ameliorating memory deficits in this murine system. 42 However, transition of findings in these animal models to human clinical trials has resulted in the development of adverse effects including hemorrhages and encephalitis, which obviously need to be prevented if this vaccination is to have any clinical utility. As well, immune tolerance to Ab as well as immunization, in the context of an aging immune system, are likewise limitations of vaccine-based interventions.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of an α synuclein sensitized dendritic cell based vaccine in a transgenic mouse model of Parkinson disease

Ugen

Lin

Bai

et al. 2015

Human Vaccines & Immunotherapeutics

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In order to develop a cell-based vaccine against the Parkinson disease (PD) associated protein a-synuclein (a-Syn) 3 peptides were synthesized based upon predicted B cell epitopes within the full length a-Syn protein sequence. These peptide fragments as well as the full length recombinant human a-Syn (rh-a-Syn) protein were used to sensitize mouse bone marrow-derived dendritic cells (DC) ex vivo, followed by intravenous delivery of these sensitized DCs into transgenic (Tg) mice expressing the human A53T variant of a-Syn. ELISA analysis and testing of behavioral locomotor function by rotometry were performed on all mice after the 5th vaccination as well as just prior to euthanasia. The results indicated that vaccination with peptide sensitized DCs (PSDC) as well as DCs sensitized by rh-a-Syn induced specific anti-a-Syn antibodies in all immunized mice. In terms of rotometry performance, a measure of locomotor activity correlated to brain dopamine levels, mice vaccinated with PSDC or rh-a-Syn sensitized DCs performed significantly better than non-vaccinated Tg control mice during the final assessment (i.e. at 17 months of age) before euthanasia. As well, measurement of levels of brain IL-1a, a cytokine hypothesized to be associated with neuroinflammation, demonstrated that this proinflammatory molecule was significantly reduced in the PSDC and rha-Syn sensitized DC vaccinated mice compared to the non-vaccinated Tg control group. Overall, a-Syn antigensensitized DC vaccination was effective in generating specific anti-a-Syn antibodies and improved locomotor function without eliciting an apparent general inflammatory response, indicating that this strategy may be a safe and effective treatment for PD.

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Therapeutically effective antibodies against amyloid-β peptide target amyloid-β residues 4–10 and inhibit cytotoxicity and fibrillogenesis

Cited by 401 publications

References 32 publications

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Evaluation of an α synuclein sensitized dendritic cell based vaccine in a transgenic mouse model of Parkinson disease

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