An amyloid-β protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease

Lord, Anna; Gumucio, Astrid; Englund, Hillevi; Sehlin, Dag; Sundquist, Valentina Screpanti; Söderberg, Linda; Möller, Christer; Gellerfors, Pär; Lannfelt, Lars; Pettersson, Frida Ekholm; Nilsson, Lars

doi:10.1016/j.nbd.2009.08.007

Cited by 109 publications

(80 citation statements)

References 50 publications

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“…80,225 This antibody was also shown to inhibit Aβ aggregation and to effectively clear soluble Aβ aggregates in vivo. 207 An interesting finding regarding the oligomer selectivity of anti-Aβ antibodies was recently reported by Lindhagen-Persson et al 205 They showed that a monoclonal IgM antibody (with 10 antigen binding regions) raised against monomeric Aβ 40 preferentially binds oligomeric Aβ. The authors attribute this to avidity effects.…”

Section: Targeting Protein Aggregatesmentioning

confidence: 86%

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Inhibition of Amyloid Formation

Härd

Lendel

2012

Journal of Molecular Biology

247

207

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Section: Targeting Protein Aggregatesmentioning

confidence: 86%

“…20 Many of these have inhibitory effects on the Aβ aggregation process in vitro. 149,[204][205][206][207] The positive effects of anti-Aβ immunotherapy in vivo is, however, believed to be the result of slightly different mechanisms of action, as described below and illustrated in Fig. 6.…”

Section: Aβ Immunotherapymentioning

confidence: 99%

Inhibition of Amyloid Formation

Härd

Lendel

2012

Journal of Molecular Biology

247

207

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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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“…The importance of soluble A ␤ aggregates in AD has highlighted the need for conformation-dependent antibodies targeting these species, to be used for immunotherapy [21] , biomarker assays [4] and the study of AD pathology and pathogenic mechanisms. Conformationdependent A ␤ antibodies have been developed for a variety of A ␤ species including A ␤ -derived diffusible ligands [22] , globulomers [8] , oligomers [6] , protofibrils [14] and fibrils [23] .…”

Section: Discussionmentioning

confidence: 99%

Heavy-Chain Complementarity-Determining Regions Determine Conformation Selectivity of Anti-Aβ Antibodies

Sehlin

Hedlund²,

Lord³

et al. 2010

Neurodegener Dis

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Background/Aims: Amyloid-β (Aβ) protofibrils are neurotoxic soluble intermediates in the Aβ aggregation process eventually forming senile plaques in Alzheimer’s disease. This Aβ species is a potential biomarker for Alzheimer’s disease and also a promising target for immunotherapy. In this study, we investigated the characteristics of conformation-dependent Aβ antibodies specific for Aβ protofibrils. Methods: Mice were immunized with Aβ protofibrils to generate hybridomas producing Aβ-specific monoclonal antibodies. Binding of antibodies to different Aβ conformations was investigated with inhibition ELISA. The antibodies’ complementarity-determining region (CDR) sequences were determined and compared. Results: A majority of the antibodies were of the IgM class, all selectively binding to aggregated Aβ. Two IgG antibodies were generated: one with selective affinity for Aβ protofibrils and the other bound Aβ in all conformations. A high degree of similarity between the heavy-chain CDRs of the conformation-dependent antibodies was found, and all high-affinity Aβ antibodies displayed a high degree of sequence similarity in the light-chain CDRs. Conclusion: Sequence similarity in the heavy-chain CDRs is associated with conformation selectivity of the antibodies, while sequence similarity in the light-chain CDRs correlates with the affinity for Aβ.

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An amyloid-β protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease

Cited by 109 publications

References 50 publications

Inhibition of Amyloid Formation

Inhibition of Amyloid Formation

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

Heavy-Chain Complementarity-Determining Regions Determine Conformation Selectivity of Anti-Aβ Antibodies

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