Protofibril-binding antibodies and their use in therapeutic and diagnostic methods for Parkinson's disease, dementia with lewy bodies and other α-synucleinopathies
Inventors
Nordström, Eva • Kasrayan, Alex • Ekberg, Monica • Screpanti Sundquist, Valentina • Lannfelt, Lars • Holmquist, Mats
Assignees
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Publication Number
US-8968734-B2
Publication Date
2015-03-03
Expiration Date
Abstract
Antibodies and fragments thereof have high affinity for human α-synuclein protofibrils and low binding of α-synuclein monomers, wherein the antibodies or fragments have specified Complementarity Determining Region (CDR) sequences. Compositions comprise such an antibody or fragment and methods of detecting α-synuclein protofibrils use such an antibody or fragment. In further embodiments, methods of preventing, delaying onset of or treating a neurodegenerative disorder with α-synuclein pathology comprise administering such an antibody or fragment, and such an antibody or fragment is used in the manufacture of a pharmaceutical composition for treatment of a neurodegenerative disorder with α-synuclein pathology. Such an antibody or fragment is used in the diagnosis or monitoring of the development of a neurodegenerative disorder with α-synuclein pathology, and in methods for reducing or inhibiting α-synuclein aggregation by administration of such an antibody or fragment.
Core Innovation
The invention concerns a monoclonal antibody or fragment thereof that selectively binds human α-synuclein protofibrils with high affinity and α-synuclein monomers with low affinity. The antibody is defined by a combination of three variable heavy (VH) complementarity determining region (CDR) sequences and three variable light (VL) CDR sequences, selected from enumerated SEQ ID NO combinations.
A central aspect is that the described antibodies are α-synuclein protofibril-selective and are associated with high affinity for HNE/ONE-stabilized α-synuclein protofibrils. The description indicates that binding selectivity is supported by competition binding and sandwich ELISA quantification, including evaluation against protofibrils and mutants such as A30P and A53T, and epitope mapping to an α-synuclein linear region 113–140.
The invention further relates to uses in detecting and addressing α-synuclein pathology by targeting protofibrils and thereby affecting oligomers. The described applications include detecting protofibrils in human dementia with Lewy bodies (DLB) extracts and evaluating selectivity in immunohistochemistry and immunoprecipitation contexts, along with in vitro inhibition of oligomerization and therapeutic approaches for preventing, delaying, or treating disease by reducing α-synuclein aggregation/oligomerization and shifting equilibrium in relation to the blood-brain barrier.
Claims Coverage
The claims are grounded in one independent claim that defines an α-synuclein protofibril-selective monoclonal antibody or fragment by explicit VH and VL CDR sequence combinations. Dependent claims extend to pharmaceutical composition and methods for detecting protofibrils, reducing α-synuclein oligomers, and treating or delaying neurodegenerative disorders associated with α-synuclein pathology.
High-affinity protofibril selectivity via enumerated VH and VL CDR combinations
A monoclonal antibody or fragment thereof having high affinity for human α-synuclein protofibrils and low affinity for α-synuclein monomers, where a combination of three VH CDR sequences and three VL CDR sequences is selected from the listed SEQ ID NO combinations.
Protofibril detection by antibody-protofibril complex formation
A method detecting α-synuclein protofibrils in a biological sample by adding a monoclonal antibody or fragment and detecting a complex formed between the protofibrils and the antibody or fragment.
Reduction of α-synuclein oligomers by administration of the antibody
A method for reducing α-synuclein oligomers in a subject by administering a monoclonal antibody or fragment as defined in the independent claim.
Treatment or delaying of α-synuclein pathology-associated neurodegenerative disorders
A method for treating or delaying a neurodegenerative disorder associated with α-synuclein pathology by administering a monoclonal antibody or fragment thereof, where the disorder is selected from Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, or multiple system atrophy.
Pharmaceutical composition including the specified antibody with a pharmaceutically acceptable carrier
A pharmaceutical composition comprising the monoclonal antibody or fragment as defined in the independent claim together with a pharmaceutically acceptable carrier.
Across the claim set, the inventive focus is an α-synuclein protofibril-selective monoclonal antibody defined by specific VH/VL CDR combinations, with dependent claims extending to pharmaceutical composition and methods for detecting protofibrils, reducing α-synuclein oligomers, and treating or delaying selected neurodegenerative disorders associated with α-synuclein pathology.
Stated Advantages
Lower effective dose due to high affinity.
Reduced inflammatory risk via reduced C1q/complement activity.
More available antibody in the periphery.
Documented Applications
Detecting protofibrils in a biological sample using an antibody or fragment to detect a protofibril-antibody complex.
Reducing α-synuclein oligomers in a subject by administering the antibody or fragment.
Treating or delaying neurodegenerative disorders associated with α-synuclein pathology, including Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy.
Imaging/localization of protofibrils using the described antibodies [procedural detail omitted for safety].
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