Anti-amyloid beta antibodies binding to a cyclic amyloid beta peptide
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Publication Number
US-10751382-B2
Publication Date
2020-08-25
Expiration Date
Abstract
The disclosure pertains to methods of treating or preventing a disease or condition associated with and/or induced by soluble A-beta oligomer such as Alzheimer's disease by administering to a subject in need thereof conformation specific and/or selective antibodies or binding fragments thereof and related products.
Core Innovation
The invention relates to two or more antibodies or antigen-binding fragments thereof that specifically and/or selectively bind cyclic compounds having amino acid sequences defined as SEQ ID NO: 2, SEQ ID NO: 10, and SEQ ID NO: 6. Each antibody includes a heavy chain variable region with complementarity determining regions CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region with complementarity determining regions CDR-L1, CDR-L2, and CDR-L3, and the antibodies have different CDRs from each other.
The disclosure also provides antibody definitions tied to CDRs mapped using the Kabat numbering scheme and includes construction and functional sequencing information for humanized antibodies, including 301-17. Variable-region sequences and CDR-defined antibody definitions are documented for antibodies raised against cyclic β-related epitope peptides corresponding to the cyclic compound amino acid sequences.
The disclosed cyclic A-beta compounds target cyclic A-beta epitopes that include residues HHQK (SEQ ID NO:1), QKLV (SEQ ID NO:5), and HDSG (SEQ ID NO:9), including cyclic compounds such as cyclo(CGHHQKG) SEQ ID NO:2, cyclo(CGQKLVG) SEQ ID NO:6, and cyclo(CGHDSGG) SEQ ID NO:10. Antibodies raised against these cyclic conformations preferentially bind oligomeric A-beta over monomers and fibrils and show negligible plaque staining.
The invention further discloses uses and compositions in which the conformation-specific antibodies are employed to inhibit A-beta propagation/aggregation in vitro and to prevent neurotoxicity and memory deficits in mouse models. The document also includes compositions and kits, immunoconjugates, and detectable labels for imaging, together with nucleic acids, vectors, and cells.
Claims Coverage
The independent claim coverage concentrates on a set of two or more antibodies or antigen-binding fragments with defined heavy- and light-chain variable regions, where each member specifically and/or selectively binds a cyclic compound by sequence (SEQ ID NO: 2, SEQ ID NO: 10, or SEQ ID NO: 6), and the members have different CDRs from each other. The inventive features therefore focus on conformation-specific binding to cyclic A-beta compound sequences and defined, mutually distinct CDRs across the antibody set.
Cdr-defined antibody set for cyclic compound binding
Two or more antibodies or antigen-binding fragments thereof each comprise a light chain variable region and a heavy chain variable region with CDR-H1, CDR-H2, CDR-H3 and CDR-L1, CDR-L2, CDR-L3, where the amino acid sequences comprise SEQ ID NOs 20-25 and the antibody specifically and/or selectively binds a cyclic compound having the amino acid sequence of SEQ ID NO: 2.
Cdr-defined antibody set for cyclic compound binding
Two or more antibodies or antigen-binding fragments thereof each comprise a light chain variable region and a heavy chain variable region with CDR-H1, CDR-H2, CDR-H3 and CDR-L1, CDR-L2, CDR-L3, where the amino acid sequences comprise SEQ ID NOs 53-58 and the antibody specifically and/or selectively binds a cyclic compound having the amino acid sequence of SEQ ID NO: 10.
Cdr-defined antibody set for cyclic compound binding
Two or more antibodies or antigen-binding fragments thereof each comprise a light chain variable region and a heavy chain variable region with CDR-H1, CDR-H2, CDR-H3 and CDR-L1, CDR-L2, CDR-L3, where the amino acid sequences comprise SEQ ID NOs 41, 42, 43, 44, 45 and 46 and the antibody specifically and/or selectively binds a cyclic compound having the amino acid sequence of SEQ ID NO: 6.
Different Cdrs across the antibody set
Each of the two or more antibodies or antigen-binding fragments thereof has different CDRs from each other.
Across the recited set, the claim requires antibodies with explicitly defined CDR sequences that specifically and/or selectively bind cyclic compounds with specified amino acid sequences (SEQ ID NO: 2, SEQ ID NO: 10, and/or SEQ ID NO: 6), and requires that the multiple antibody members have different CDRs from each other.
Stated Advantages
Preferential binding to oligomeric A-beta over monomers and fibrils.
Negligible plaque staining.
Inhibition of A-beta propagation/aggregation in vitro.
Prevention of neurotoxicity in mouse models.
Prevention of memory deficits in mouse models.
Prevention of AβO-induced cognitive deficits in novel object recognition after ICV co-administration with selected antibodies.
Synaptic preservation in the hippocampus as indicated by PSD-95 and SNAP-25 biomarker analyses for effective antibodies.
Reduced inflammation in the hippocampus as indicated by TNF-α biomarker analyses for effective antibodies.
Documented Applications
Treatment and prevention of soluble A-beta oligomer-associated conditions, including Alzheimer’s disease and cognitive deficits.
Imaging via detectable labels including positron-emitting radionuclides (PET imaging).
ICV co-administration in mouse novel object recognition experiments where Aβ oligomers are used and antibodies prevent AβO-induced cognitive deficits.
Hippocampal biomarker analyses in mice for PSD-95, SNAP-25, and TNF-α following antibody effectiveness tied to binding characterization.
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