α-synuclein protofibril-binding antibodies
Inventors
Nordström, Eva • SIGVARDSON, Jessica • Nygren, Patrik
Assignees
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Publication Number
US-11339212-B2
Publication Date
2022-05-24
Expiration Date
Abstract
The present disclosure is based, in part, on the discovery of antibodies that selectively targets human α-synuclein aggregates such as oligomers/protofibrils, such as BAN0805. BAN0805 has a lower tendency to bind to the undesired monomeric α-synuclein target as compared to mouse monoclonal antibody mAb47.
Core Innovation
Human α-synuclein protofibril-selective antibodies are disclosed, including BAN0805, which bind preferentially to α-synuclein protofibrils relative to monomeric α-synuclein. The antibody embodiments are defined by specific heavy chain and light chain amino acid sequences identified as SEQ ID NOs, including BAN0805 having a heavy chain comprising SEQ ID NO:3 and a light chain comprising SEQ ID NO:4, as well as embodiments having heavy chain and light chain amino acid sequences comprising SEQ ID NO:1 and SEQ ID NO:2.
The disclosed antibodies show stronger binding and affinity for protofibrils than for monomers, with reported selectivity improvements relative to a comparator mAb47. The document reports quantitative selectivity differences using inhibition ELISA and Biacore SPR, including reported fold-differences for binding to PF versus monomeric α-synuclein.
The document also reports lack of detectable cross-reactivity to β/γ-synuclein monomers and Aβ-protofibrils. Biophysical characterization and stability-related evaluations are described, including SEC-MALS results and stress-tolerance after thermal and freeze/thaw conditions, together with nucleic acids encoding the antibodies and a neurodegenerative disorder treatment context.
Claims Coverage
The independent claims cover three inventive features: two specific antibody heavy/light chain sequence pairs and one nucleic acid encoding a polypeptide selected from SEQ ID NOs. Across the claim families, inventive features are tied to defined sequence identifiers, with dependent refinements referencing protofibril-selective binding constraints and sequence-set restrictions.
Specific heavy and light chain sequences (SEQ ID NO:1 and SEQ ID NO:2)
An antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO: 2.
Specific heavy and light chain sequences (SEQ ID NO:3 and SEQ ID NO:4)
An antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:3 and a light chain comprising the amino acid sequence of SEQ ID NO:4.
Nucleic acid encoding a polypeptide selected from SEQ ID NOs: 1-4
A nucleic acid encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-4.
Overall, the claim coverage is grounded on antibodies defined by specific SEQ ID NO heavy/light chain amino acid sequences and on nucleic acids encoding polypeptides selected from SEQ ID NO ranges. Dependent refinements further specify protofibril-selective binding requirements and additional SEQ ID NO group restrictions.
Stated Advantages
Protofibril binding selectivity over monomeric α-synuclein, with reported fold-differences in affinity and selectivity.
Notably improved protofibril selectivity relative to a comparator mAb47, based on inhibition ELISA and Biacore SPR selectivity results.
Lack of detectable cross-reactivity to β/γ-synuclein monomers and Aβ-protofibrils.
Antibody stability and stress tolerance characterized by SEC-MALS and thermal and freeze/thaw evaluations.
Documented Applications
Treatment context for neurodegenerative disorders, including Parkinson’s disease (PD), is discussed in the document.
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