Anti-amyloid beta antibodies binding to a cyclic amyloid beta peptide
Inventors
Cashman, Neil R. • Plotkin, Steven S.
Assignees
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Publication Number
US-10774120-B2
Publication Date
2020-09-15
Expiration Date
Abstract
The disclosure pertains to conformational epitopes in A-beta, antibodies thereto and methods of making and using immunogens and antibodies specific thereto.
Core Innovation
The invention relates to a cyclic A-beta peptide comprising the amino acid sequence of SEQ ID NO:2 and to antibodies that are conformation specific and/or selective. The disclosure identifies a conformational A-beta epitope centered on residues HHQK (SEQ ID NO:1) including a related segment HQKL (SEQ ID NO:20), and states that the epitope is selectively accessible in A-beta oligomers versus A-beta monomers and A-beta fibrils. It proposes cyclic and conformationally constrained cyclic A-beta-mimicking compounds designed to present a distinct antigenic surface relative to linear and fibril ensembles.
The cyclic peptide is described as locking alternate curvature or dihedral-angle features associated with the targeted epitope region, with linker chemistry used to reduce structural overlap with linear and fibril ensembles by enforcing constrained conformation. The comparison focuses on dihedral-angle distributions, Ramachandran phi/psi angles, side-chain entropy, solvent accessibility, ensemble RMSD clustering/overlap, and overlap metrics relative to a fibril structure. The disclosure states that structural analyses support distinct antigenic presentation and that the cyclic ensemble is globally distinct.
The disclosure further states that immunogens based on the cyclic compound generate antibodies that preferentially bind the cyclic epitope and A-beta oligomers over A-beta monomers and A-beta fibrils. It asserts that such antibodies show reduced or absent plaque binding in AD tissue and that they inhibit oligomer propagation or aggregation and oligomer-induced neuronal toxicity. It also describes conformation-selective antibody features including antibody formats and CDR sequence information, and states downstream applications including immunoconjugates with positron-emitting radionuclides for PET imaging as well as kits, compositions, and nucleic acids for detection and therapy/immunization.
Claims Coverage
The provided independent claim covers a conformation specific and/or selective antibody or antigen-binding fragment that specifically and/or selectively binds a cyclic A-beta peptide of SEQ ID NO: 2, with defined heavy-chain and light-chain variable region CDR amino-acid sequences. The claim set further refines binding selectivity toward an A-beta oligomer, constrains antibody format, and defines downstream immunoconjugate and kit embodiments with detectable labeling.
Cyclic A-beta-peptide binding antibody with specified variable-region CDR sequences
An isolated conformation specific and/or selective antibody or antigen-binding fragment that specifically and/or selectively binds to a cyclic A-beta peptide comprising the amino acid sequence of SEQ ID NO: 2, comprising a light chain variable region and a heavy chain variable region, with heavy-chain and light-chain CDR amino-acid sequences comprising SEQ ID NOs: 22-27.
Oligomer-selective binding
The antibody or antigen-binding fragment further specifically and/or selectively binds to an A-beta oligomer.
Monoclonal and/or humanized antibody form
The antibody or antigen-binding fragment is specified to be monoclonal or humanized.
Antigen-binding fragment and multimer formats
The antibody or antigen-binding fragment is specified as a Fab, Fab’, F(ab’)2, scFv, dsFv, ds-scFv, nanobody, minibody, diabody, or a dimer or multimer of such fragments.
Immunoconjugate with positron-emitting radionuclide detectable label
An immunoconjugate in which the detectable label is a positron-emitting radionuclide.
Diagnostic or therapeutic kit format incorporating antibody or immunoconjugate
A diagnostic or therapeutic kit that includes either the antibody or antigen-binding fragment of the first claim or the immunoconjugate incorporating the positron-emitting radionuclide label.
Across the provided claim set, the coverage centers on conformation specific and/or selective antibodies or antigen-binding fragments that bind the cyclic A-beta peptide of SEQ ID NO:2 using specified heavy- and light-chain CDR sequences. Dependent coverage further narrows to A-beta oligomer binding, specifies antibody and fragment formats, and defines immunoconjugate and kit embodiments.
Stated Advantages
Generates antibodies that preferentially bind the cyclic epitope and A-beta oligomers over A-beta monomers and A-beta fibrils.
Shows reduced or absent plaque binding in AD tissue.
Inhibits oligomer propagation or aggregation.
Inhibits oligomer-induced neuronal toxicity.
Preferential binding to the cyclic peptide over the linear peptide.
Selectivity for binding to A-beta oligomers over monomers.
Functional inhibition of A-beta aggregation.
Documented Applications
PET imaging using immunoconjugates with positron-emitting radionuclides.
Detection and therapy/immunization using kits, compositions, and nucleic acids/vectors/cells.
Generation and screening of mouse monoclonal antibodies for preferential binding to the cyclic A-beta peptide over the linear peptide.
Binding/selectivity assays for antibody recognition of A-beta oligomers versus monomers.
Functional inhibition of A-beta aggregation assays.
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