Antibodies and vaccines for use in therapeutic and diagnostic methods for α-synuclein-related disorders
Inventors
Lannfelt, Lars • Bergström, Joakim • Ingelsson, Martin • Gellerfors, Pär
Assignees
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Publication Number
US-9315569-B2
Publication Date
2016-04-19
Expiration Date
Abstract
Methods of treating or delaying onset of a neurodegenerative disorder with α-synuclein pathology in an individual comprise administering an antibody which is produced from a stabilized soluble α-synuclein oligomer and capable of binding a stabilized soluble α-synuclein oligomer, the stabilized soluble α-synuclein oligomer having a lower formation rate to a non-soluble aggregated form than a non-stabilized soluble oligomer of the α-synuclein. The antibody has been collected from a non-human animal to which stabilized soluble α-synuclein oligomer had been administered or has been produced by hybridoma technology, phage display, ribosome display, mammalian cell display or bacterial display, and the disorder with α-synuclein pathology is characterized by deposition of Lewy bodies and Lewy neurites or is selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), the Lewy body variant of Alzheimer's disease, and multiple system atrophy (MSA).
Core Innovation
The patent relates to treating a neurodegenerative disorder with α-synuclein pathology in an individual, or delaying onset of such a disorder in an individual at risk. The disorders are selected from Parkinson's disease (PD), dementia with Lewy bodies (DLB), the Lewy body variant of Alzheimer's disease, and multiple system atrophy (MSA). The treatment comprises administering an antibody produced from a stabilized soluble α-synuclein oligomer or stabilized soluble α-synuclein protofibril that is capable of binding stabilized soluble α-synuclein oligomers or protofibrils, respectively.
A central element is the nature of the antigen used to produce the antibody. The stabilized soluble α-synuclein oligomer or protofibril comprises soluble α-synuclein modified with 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, or a combination thereof, and has a lower formation rate to a non-soluble aggregated form than a non-stabilized soluble oligomer or protofibril. The stabilized soluble oligomer or protofibril comprises wild type α-synuclein of SEQ ID NO: 1, and the antibody is capable of binding wild type soluble α-synuclein oligomers or protofibrils.
In the protofibril-based approach, the antibody has higher binding strength to soluble α-synuclein protofibril as compared with binding strength to α-synuclein monomers and as compared with binding strength to insoluble α-synuclein fibrils. Antibody sourcing and production are also defined, including collection from a non-human animal to which stabilized soluble α-synuclein protofibril had been administered, or production by hybridoma technology, phage display, ribosome display, mammalian cell display, or bacterial display.
Claims Coverage
The provided excerpt contains three independent claims. Across these independent claims, the key inventive features are administering an antibody that is produced from stabilized soluble α-synuclein oligomers or stabilized soluble α-synuclein protofibrils, where stabilization is defined by 4-hydroxy-2-nonenal and/or 4-oxo-2-nonenal modifications and is characterized by a lower formation rate to non-soluble aggregates than non-stabilized forms; and requiring that the antibody binds wild type soluble α-synuclein, with additional selectivity and production/sourcing constraints in the protofibril-specific independent claim.
Treating or delaying α-synuclein pathology using antibody from stabilized soluble oligomer
A method of treating a neurodegenerative disorder with α-synuclein pathology in an individual, or delaying onset of a neurodegenerative disorder with α-synuclein pathology in an individual at risk of developing the disorder, wherein the disorder with α-synuclein pathology is selected from Parkinson's disease (PD), dementia with Lewy bodies (DLB), the Lewy body variant of Alzheimer's disease, and multiple system atrophy (MSA), comprising administering to the individual an antibody produced from a stabilized soluble α-synuclein oligomer and capable of binding a stabilized soluble α-synuclein oligomer, the stabilized soluble α-synuclein oligomer comprising a soluble α-synuclein oligomer modified with 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, or a combination thereof and having a lower formation rate to a non-soluble aggregated form than a non-stabilized soluble oligomer of the α-synuclein, and the α-synuclein oligomer comprising wild type α-synuclein of SEQ ID NO: 1, wherein the antibody is capable of binding wild type soluble α-synuclein oligomers.
Lewy body and Lewy neurite deposition treated using antibody from stabilized soluble oligomer
A method of treating a neurodegenerative disorder with α-synuclein pathology in an individual, or delaying onset of a neurodegenerative disorder with α-synuclein pathology in an individual at risk of developing the disorder, wherein the disorder with α-synuclein pathology is characterized by deposition of Lewy bodies and Lewy neurites in an individual, comprising administering to the individual an antibody produced from a stabilized soluble α-synuclein oligomer and capable of binding a stabilized soluble α-synuclein oligomer, the stabilized soluble α-synuclein oligomer comprising a soluble α-synuclein oligomer modified with 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, or a combination thereof and having a lower formation rate to a non-soluble aggregated form than a non-stabilized soluble oligomer of the α-synuclein, and the α-synuclein oligomer comprising wild type α-synuclein of SEQ ID NO: 1, wherein the antibody is capable of binding wild type soluble α-synuclein oligomers.
Treating using antibody from stabilized soluble protofibril with higher selectivity
A method of treating a neurodegenerative disorder with α-synuclein pathology in an individual, or delaying onset of a neurodegenerative disorder with α-synuclein pathology in an individual at risk of developing the disorder, wherein the disorder with α-synuclein pathology is selected from Parkinson's disease (PD), dementia with Lewy bodies (DLB), the Lewy body variant of Alzheimer's disease, and multiple system atrophy (MSA), comprising administering to the individual an antibody which is produced from a stabilized soluble α-synuclein protofibril and capable of binding a stabilized soluble α-synuclein protofibril, the stabilized soluble α-synuclein protofibril comprising a soluble α-synuclein protofibril modified with 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, or a combination thereof and having a lower formation rate to a non-soluble aggregated form than a non-stabilized soluble protofibril of the α-synuclein, and the α-synuclein protofibril comprising wild type α-synuclein of SEQ ID NO: 1, wherein the antibody has been collected from a non-human animal to which stabilized soluble α-synuclein protofibril had been administered or wherein the antibody has been produced by hybridoma technology, phage display, ribosome display, mammalian cell display or bacterial display, and wherein the antibody is capable of binding wild type soluble α-synuclein protofibrils, has higher binding strength to soluble α-synuclein protofibril as compared with binding strength to α-synuclein monomers, and has higher binding strength to soluble α-synuclein protofibril as compared with binding strength to insoluble α-synuclein fibrils.
Across the independent claims, the invention centers on administering an antibody that binds stabilized soluble α-synuclein oligomers or stabilized soluble α-synuclein protofibrils, where stabilization is achieved by modification with 4-hydroxy-2-nonenal and/or 4-oxo-2-nonenal and is characterized by a lower formation rate to non-soluble aggregates than non-stabilized forms, using wild type α-synuclein of SEQ ID NO: 1; the protofibril-based independent claim additionally requires specified antibody sourcing and production approaches and higher binding strength for protofibrils versus monomers and insoluble fibrils.
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