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-10759837-B2
Publication Date
2020-09-01
Expiration Date
Abstract
The disclosure pertains to epitopes identified in A-beta including conformational epitopes, antibodies thereto and methods of making and using immunogens and antibodies specific thereto.
Core Innovation
The invention provides an oligomer-selectively accessible, conformational Aβ epitope centered on residues QKLV (SEQ ID NO:1; residues 15–18 of Aβ). The epitope is identified via computational predictions of misfolded and/or disrupted regions in fibril/oligomer contexts, and is presented in a cyclized peptide immunogen such as cyclo(CGQKLVG) (SEQ ID NO:3) that constrains specific side-chain/dihedral conformations.
The cyclic epitope immunogens are designed to increase curvature and solvent exposure, so that antibodies preferentially bind Aβ oligomers over Aβ monomers and Aβ fibrils. The document further reports minimal/neglectable plaque binding, and describes linker embodiments for cyclic epitope compounds including PEG and cysteine functionalizable moieties.
The invention provides cyclic epitope compounds and immunogens with embodiments for immunogen coupling to carriers and optional adjuvants. The document also describes isolated antibodies and antibody formats, including antigen-binding fragments and immunoconjugates, for diagnostics and therapeutics.
Claims Coverage
The independent claims center on one inventive feature: an isolated antibody or antigen-binding fragment that specifically binds a cyclic Aβ peptide comprising SEQ ID NO: 3, with defined heavy- and light-chain variable regions and CDR amino-acid sequences. Dependent claims further specify variable-region embodiments, antibody/fragment formats, immunoconjugates, and compositions.
Cyclic Aβ peptide-specific antibody with defined CDR sets
An isolated antibody or antigen-binding fragment that specifically binds a cyclic Aβ peptide comprising the amino acid sequence of SEQ ID NO: 3, comprising a light chain variable region and a heavy chain variable region with CDR-H1, CDR-H2, and CDR-H3 and CDR-L1, CDR-L2, and CDR-L3 amino acid sequences, wherein the CDR sequences are one of two alternative specified sets.
Antibody A with specified heavy- and light-chain variable regions
An antibody or antigen-binding fragment in which the heavy chain variable region and light chain variable region comprise the amino acid sequences of SEQ ID NO: 18 and SEQ ID NO: 20, respectively.
Antibody B with specified heavy- and light-chain variable regions
An antibody or antigen-binding fragment in which the heavy chain variable region and light chain variable region comprise the amino acid sequences of SEQ ID NO: 28 and SEQ ID NO: 30, respectively.
Antibody/fragment formats and multimerization states
An antibody or antigen-binding fragment formatted as one of Fab, Fab′, F(ab′)2, scFv, dsFv, ds-scFv, nanobody, minibody, diabody, or a dimer or multimer thereof.
Immunoconjugate with positron-emitting radionuclide label
An immunoconjugate in which the detectable label includes a positron-emitting radionuclide.
Composition including the antibody and/or immunoconjugate
A composition including the antibody and/or the immunoconjugate, optionally together with a diluent.
Overall, the claim coverage centers on cyclic Aβ peptide (SEQ ID NO: 3)-specific isolated antibodies or antigen-binding fragments with defined CDR sequences in two alternative sets, refined by two specific variable-region embodiments. Coverage further specifies antibody and fragment formats, an immunoconjugate with a positron-emitting radionuclide label, and compositions including the antibody and/or immunoconjugate.
Stated Advantages
Preferentially elicit antibodies that bind Aβ oligomers over Aβ monomers and Aβ fibrils.
Achieve minimal/neglectable plaque binding.
Enable diagnostics for detecting Aβ oligomer in samples such as CSF/brain extract, including imaging/labeling with positron-emitting radionuclides.
Provide therapeutics by inhibiting Aβ oligomer propagation/aggregation and treating AD and related amyloid diseases.
Documented Applications
Diagnostics by detecting Aβ oligomer in samples such as CSF/brain extract.
Imaging/labeling using positron-emitting radionuclides (including PET imaging).
Therapeutics by inhibiting Aβ oligomer propagation/aggregation and treating Alzheimer’s disease and related amyloid diseases.
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