Protofibril-binding antibodies and their use in therapeutic and diagnostic methods for Parkinson's disease, dementia with lewy bodies and other α-synucleinopathies
Inventors
NORDSTROEM EVA, null • Nordström, Eva • Kasrayan, Alex • Ekberg, Monica • Sundquist, Valentina Screpanti • Lannfelt, Lars • Holmquist, Mats
Assignees
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Publication Number
US-8632776-B2
Publication Date
2014-01-21
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 relates to an isolated antibody or fragment thereof that has high affinity for human α-synuclein protofibrils while exhibiting low binding of human α-synuclein monomers. The antibody is defined by a specific combination of three variable heavy (VH) CDR sequences and three variable light (VL) CDR sequences selected from defined Kabat SEQ ID sequence combinations.
The disclosed antibodies target protofibrils and/or oligomers of human α-synuclein, including protofibril/oligomer forms stabilized by aldehydes such as HNE and ONE. The document also describes targeting mutant forms of α-synuclein including A30P, A53T, and E46K, and maps epitopes to a linear α-synuclein amino acid region 113–140 with example epitope subregions including 125–131, 121–124, 121–127, 113–123, and 136–140.
The invention further includes uses for detecting, quantifying, and inhibiting pathological α-synuclein protofibrils and oligomers. It describes diagnostic detection such as sandwich ELISA and other immunoassay formats, along with imaging approaches using radiolabels, and therapeutic use aimed at reducing α-synuclein oligomers in a subject. The document also describes reduced or engineered C1q/complement activation to address inflammatory risk, and assay-based evaluation of protofibril and oligomer recognition.
Claims Coverage
The independent claim covers an isolated antibody or fragment that is protofibril-selective for human α-synuclein with low monomer binding, and it is limited by a defined structure: a combination of three VH CDR sequences and three VL CDR sequences selected from enumerated SEQ ID combinations. The claim set centers on binding specificity and an exact VH/VL CDR sequence combination selection; dependent claims further narrow the SEQ ID combinations and add use/formulation and method coverage.
Protofibril-selective high-affinity antibody with low monomer binding
An isolated antibody or fragment thereof having high affinity for human α-synuclein protofibrils and low binding of α-synuclein monomers.
Defined three-vh CDR and three-vl CDR sequence combinations selected from enumerated SEQ IDs
The antibody or fragment has a combination of three variable heavy (VH) CDR sequences and three variable light (VL) CDR sequences selected from the enumerated combinations of SEQ ID NOS: 22, 28, 35, 41, 47 and 50; 23, 29, 36, 42, 47 and 50; 24, 30, 37, 43, 48 and 51; 25, 31, 38, 44, 47 and 52; 26, 32, 39, 45, 47 and 53; 23, 33, 37, 43, 48 and 54; and 27, 34, 40, 46, 49 and 55.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition that includes an antibody or fragment as defined by the independent claim together with a pharmaceutically acceptable carrier.
Detecting α-synuclein protofibrils via complex formation with an antibody or fragment
A method detects α-synuclein protofibrils by contacting a biological sample with an antibody or fragment and detecting formation of a complex between the protofibrils and the antibody or fragment.
Reducing α-synuclein oligomers in a subject by administering an antibody or fragment
A method reduces the amount of α-synuclein oligomers in a subject by administering an antibody or fragment to the subject.
Specific enumerated CDR sequence combination variant
The antibody or fragment’s CDR region sequence combination comprises SEQ ID NOS: 22, 28, 35, 41, 47 and 50.
Overall, the claim coverage is anchored in a protofibril-selective, high-affinity isolated antibody defined by a specific combination of three VH CDR and three VL CDR sequences chosen from enumerated SEQ ID combinations. Dependent coverage includes specific SEQ ID variants, a pharmaceutical composition with a pharmaceutically acceptable carrier, diagnostic detection by detecting complex formation in a biological sample, and therapeutic reduction of α-synuclein oligomers by administering the antibody or fragment.
Stated Advantages
Reduced required dose, as stated in the document.
Ability to clear pathogenic α-synuclein protofibrils.
Reduced inflammatory risk via reduced or engineered C1q/complement activation.
Ability to detect and quantify protofibrils while having negligible monomer interference, as stated in the document.
Use in imaging and monitoring α-synuclein protofibrils/oligomers, as stated in the document.
Inhibition of α-synuclein oligomerization signal, as stated in the document.
Documented Applications
Detection and quantification of α-synuclein protofibrils, including use of sandwich ELISA and immunoassay formats described in the document.
Imaging α-synuclein protofibrils/oligomers using radiolabels described in the document.
Monitoring α-synuclein protofibrils/oligomers, as described in the document.
Therapeutic reduction of α-synuclein oligomers in a subject by administering an antibody or fragment, including use cases described for α-synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB).
Inhibition of α-synuclein oligomerization, as described in the document.
Use across α-synucleinopathies including PD and DLB, as described in the document.
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