Protofibril-binding antibodies and their use in thereapeutic and diagnostic methods for parkinson's disease, dementia with lewy bodies and other alpha-synucleinopathies

Inventors

Nordström, Eva • Kasrayan, Alex • Ekberg, Monica • Screpanti Sundquist, Valentina • Lannfelt, Lars • Holmquist, Mats

Assignees

Bioarctic AB

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 relates to protofibril-binding b1-synuclein antibodies and antibody fragments that bind human b1-synuclein protofibrils with high affinity and exhibit low binding affinity to b1-synuclein monomers. The antibodies are defined by a combination of three variable heavy (VH) CDR sequences and three variable light (VL) CDR sequences selected from enumerated combinations of SEQ ID NOS, and the structure-based definition is used to specify protofibril-binding antibodies and fragments.

The described antibodies include target epitope regions within b1-synuclein, with example linear epitope regions spanning amino acid region 1130 and additional example epitope selections within regions such as 1251, 1214, 1217, 1211, 1133, and 1360. The patent content further describes CDR sequence selection rules for VH-CDR1/2/3 and VL-CDR1/2/3, including multiple SEQ ID NO sets and similarity thresholds.

The invention is directed to reducing or inhibiting b1-synuclein aggregation, and to preventing, delaying onset, or treating b1-synucleinopathies in individuals. The disclosed intended clinical and research uses include treating neurodegenerative disorders characterized by deposition of Lewy bodies and Lewy neurites, including Parkinsons disease (PD), dementia with Lewy bodies (DLB), Lewy body variant of Alzheimers disease, and multiple system atrophy (MSA), as well as diagnostic/imaging/monitoring uses based on detection and quantification of protofibrils in samples using immunoassays.

Claims Coverage

The partial claim set includes three independent method claims, each requiring an antibody or fragment with high affinity for human b1-synuclein protofibrils, low affinity for b1-synuclein monomers, and a defined combination of three VH CDR sequences and three VL CDR sequences selected from enumerated SEQ ID NO combinations.

Across the independent claims, the inventive coverage centers on administering antibody or fragments defined by a high-affinity, low-monomer-affinity binding profile for human b1-synuclein protofibrils, with the binding specificity implemented through enumerated combinations of three VH CDR and three VL CDR sequences.

Stated Advantages

Documented Applications