Compositions comprising cyclic peptides derived from an A-beta peptide
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Publication Number
US-11779629-B2
Publication Date
2023-10-10
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 document describes therapeutic and diagnostic approaches for soluble Aβ oligomer-associated diseases, including Alzheimer’s disease. It provides conformation-selective antibodies and binding fragments raised against cyclic, immunogenic Aβ epitope conformations comprising cyclo(CGHHQKG) (SEQ ID NO:2), cyclo(CGQKLVG) (SEQ ID NO:6), and cyclo(CGHDSGG) (SEQ ID NO:10). These antibodies preferentially bind oligomeric Aβ over monomeric and fibrillar forms and are described as lacking or having negligible plaque binding.
The document states that the conformation-selective antibodies inhibit Aβ aggregation and propagation in vitro and reduce neuronal toxicity. It further states that treatment can prevent AβO-induced memory deficits in a mouse Novel Object Recognition assay (NOR). The disclosure also includes antibody variable-region sequence information for antibodies raised against cyclo(CGQKLVG), including multiple heavy and light chain variants, isotypes, CDR delineation, and Kabat-numbered CDR sequences for humanized 301-17 constructs.
The document also discloses diagnostic and detection uses based on forming antibody complexes and imaging with labeled immunoconjugates. It further reports recombinant antibody binding characterization to Aβ oligomers and cyclopeptide epitopes using ProteOn, MAAS-2, and Biacore, including single-cycle analysis and KD values, together with dot blot specificity for oligomeric but not monomeric or fibrillar Aβ.
Claims Coverage
Two independent claim themes are identified in the provided excerpts: one recites a composition based on a combination of cyclic immunogens, and another centers on conformation-selective antibodies raised against cyclic Aβ epitope conformations.
Combination immunogen composition with cyclic compounds
A composition comprising a combination of two or more different immunogens selected from cyclo(CGHHQKG) (SEQ ID NO: 2), cyclo(CGQKLVG) (SEQ ID NO: 6), and cyclo(CGHDSGG) (SEQ ID NO: 10).
Conformation-selective antibodies to cyclic Aβ epitope conformations
Antibodies and binding fragments raised against cyclic, immunogenic Aβ epitope conformations comprising cyclo(CGHHQKG), cyclo(CGQKLVG), and cyclo(CGHDSGG), with preferential binding to oligomeric Aβ over monomeric and fibrillar forms.
The claim coverage centers on a cyclic immunogen composition and on conformation-selective antibodies or binding fragments that target the specified cyclic Aβ epitope conformations.
Stated Advantages
Preferential binding to oligomeric Aβ over monomers and fibrils, with lack or negligible plaque binding.
Inhibition of Aβ aggregation and propagation in vitro.
Reduction of neuronal toxicity.
Prevention of AβO-induced memory deficits in a mouse Novel Object Recognition assay (NOR).
Detection of Aβ oligomers using antibody complex formation and imaging with labeled immunoconjugates, including PET imaging with positron-emitting radionuclides.
Selective dot blot binding to oligomeric but not monomeric or fibrillar Aβ.
Documented Applications
Therapeutic use for soluble Aβ oligomer-associated diseases, including Alzheimer’s disease, using conformation-selective antibodies or binding fragments.
Diagnostic detection of Aβ oligomers via antibody complex formation and imaging with labeled immunoconjugates, including PET imaging using positron-emitting radionuclides.
Behavioral and functional assessment in a mouse Novel Object Recognition assay (NOR) to evaluate prevention of AβO-induced memory deficits.
Sequence characterization of antibody variable regions, including IMGT/LIGM-DB CDR delineation and Kabat-numbered CDR sequences for humanized 301-17 constructs.
Recombinant antibody binding characterization to Aβ oligomers and cyclopeptide epitopes using ProteOn, MAAS-2, and Biacore, together with dot blot specificity.
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