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-9084832-B2
Publication Date
2015-07-21
Expiration Date
Abstract
In an in vivo method for detecting α-synuclein protofibrils in human tissue, an antibody or fragment thereof is administered to a human. The antibody or fragment is labelled with a detectable label. A complex formed between the antibody or fragment and α-synuclein protofibrils in the human tissue is detected. The antibody or fragment has high affinity for human α-synuclein protofibrils and low affinity for α-synuclein monomers and has a combination of three specified variable heavy (VH) CDR sequences and three specified variable light (VL) CDR sequences.
Core Innovation
The invention relates to anti-b1-synuclein protofibril antibodies and fragments that preferentially bind human b1-synuclein protofibrils. The antibodies have high affinity for human b1-synuclein protofibrils and low affinity for b1-synuclein monomers, so that a complex forms with protofibrils while minimizing binding to monomers.
The antibodies are defined by specific combinations of variable heavy (VH) CDR sequences and variable light (VL) CDR sequences selected from multiple SEQ ID set combinations. The protofibril-binding epitope is localized to a linear epitope within amino acids 113f140, with examples including 125131, 121124, 121127, 121131, 113123, and 136140.
The invention further includes an in vivo method for detecting b1-synuclein protofibrils in human tissue by administering a labelled antibody or fragment and detecting the antibodyprotofibril complex in the human tissue. The description also includes monitoring by quantifying the detected complex and repeating administration to assess treatment effect, and it situates the invention in b1-synucleinopathies including Parkinsons disease and dementia with Lewy bodies.
Claims Coverage
The provided content describes one independent claim set with three inventive features, centered on an in vivo detection method using a labelled antibody or fragment with protofibril-selective binding and specified VH/VL CDR sequence combinations.
In vivo detection of b1-synuclein protofibrils using labelled protofibril-selective antibody
A method for detecting b1-synuclein protofibrils in human tissue by administering a labelled antibody or fragment to a human and detecting a complex formed between the labelled antibody or fragment and b1-synuclein protofibrils in the human tissue.
High affinity for protofibrils and low affinity for monomers
The antibody or fragment has high affinity for human b1-synuclein protofibrils and low affinity for b1-synuclein monomers.
Specific VH and VL CDR sequence combination for protofibril binding
The antibody or fragment has a combination of three variable heavy (VH) CDR sequences and three variable light (VL) CDR sequences selected from the listed SEQ ID combinations.
Coverage centers on an in vivo detection method that depends on a labelled antibody or fragment with protofibril-selective binding and a specified VH/VL CDR sequence combination.
Stated Advantages
Lower effective dose is emphasized via reduced monomer binding.
Reduced inflammatory risk is emphasized via reduced C1q/complement activation.
High selectivity for b1-synuclein protofibrils over b1-synuclein monomers is emphasized.
Documented Applications
In vivo detection of b1-synuclein protofibrils in human tissue for diagnosis or monitoring associated with b1-synuclein pathology, including Parkinsons disease and dementia with Lewy bodies.
Monitoring treatment effect by quantifying a detected antibody-b1-synuclein protofibril complex and repeating administration to detect a newly formed complex.
Therapeutic aims to prevent, delay, or treat b1-synucleinopathies and inhibit aggregation.
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