Mimotopes of alpha-synuclein and vaccines thereof for the treatment of synucleinopathy
Inventors
Mandler, Markus • Weninger, Harald • Santic, Radmila • Kopinits, Edith
Assignees
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Publication Number
US-11534484-B2
Publication Date
2022-12-27
Expiration Date
Abstract
A method of treating a synucleinopathy with a peptide (C)DQPVLPD (SEQ ID NO: 59), (C)DMPVLPD (SEQ ID NO: 60), (C)DSPVLPD (SEQ ID NO: 61), (C)DQPVLPDN (SEQ ID NO: 64), (C)DMPVLPDN (SEQ ID NO: 65), (C)DSPVLPDN (SEQ ID NO: 66), (C)HDRPVTPD (SEQ ID NO: 70), (C)DRPVTPD (SEQ ID NO: 71), (C)DVPVLPD (SEQ ID NO: 72), (C)DTPVYPD (SEQ ID NO: 73), (C)DTPVIPD (SEQ ID NO: 74), (C)HDRPVTPDN (SEQ ID NO: 75), (C)DRPVTPDN (SEQ ID NO: 76), (C)DVPVLPDN (SEQ ID NO: 78), (C)DTPVYPDN (SEQ ID NO: 79), (C)DQPVLPDG (SEQ ID NO: 81), (C)DMPVLPDG (SEQ ID NO: 82), (C)DSPVLPDG (SEQ ID NO: 83), (C)DHPVHPDS (SEQ ID NO: 86), (C)DMPVSPDR (SEQ ID NO: 87), (C)DRPVYPDI (SEQ ID NO: 90), (C)DHPVTPDR (SEQ ID NO: 91), (C)DTPVLPDS (SEQ ID NO: 93), (C)DMPVTPDT (SEQ ID NO: 94), (C)DAPVTPDT (SEQ ID NO: 95), (C)DSPVVPDN (SEQ ID NO: 96), (C)DLPVTPDR (SEQ ID NO: 97), (C)DSPVHPDT (SEQ ID NO: 98), (C)DAPVRPDS (SEQ ID NO: 99), (C)DMPVWPDG (SEQ ID NO: 100), (C)DRPVQPDR (SEQ ID NO: 102), (C)YDRPVQPDR (SEQ ID NO: 103), (C)DMPVDADN (SEQ ID NO: 105), DQPVLPD(C) (SEQ ID NO: 106), and DMPVLPD(C) (SEQ ID NO: 107.
Core Innovation
The invention relates to synucleinopathy treatment using vaccine compositions that comprise peptide-based immunogens. The peptide sequences are modeled on an alpha-synuclein epitope, specifically DMPVDPDN (SEQ ID NO:1), and are described as mimotope peptides. These mimotopes elicit antibodies that bind alpha-synuclein while showing reduced or limited cross-reactivity with beta-synuclein.
The disclosure describes peptide-to-carrier vaccine formulations in which the mimotope peptide is coupled to a pharmaceutically acceptable carrier. Keyhole limpet hemocyanin (KLH) and linker approaches are described, including NHS-poly(ethylene oxide) (NHS-PEO) linker variants. The disclosed peptide sets include multiple sequence variants, including options involving cysteine at an N- and/or C-terminus and terminal cyclization.
The disclosure supports the described concept through characterization and in vivo experimentation. It describes generation and binding/inhibition characterization of an alpha-synuclein epitope-specific monoclonal antibody (AFFiRiS3/9), screening of mimotopes using phage display libraries (Ph.D.7 and Ph.D.12), and antibody binding assessment including ELISA-based characterization and cross-reactivity results. It further describes in situ immunohistochemistry detection of alpha-syn positive inclusions in transgenic mouse brain sections expressing human alpha-synuclein.
Claims Coverage
The partial content identifies one independent claim directed to a peptide coupled to a pharmaceutically acceptable carrier, where the peptide is up to 20 amino acid residues and is selected from specified SEQ ID/SEG ID numbers. The dependent claims refine this framework by specifying the carrier, covalent coupling, an NHS-poly(ethylene oxide) linker, vaccine compositions, and optional adjuvant inclusion.
Carrier-coupled short peptide selected from specified SEQ/SEG IDs
A peptide coupled to a pharmaceutically acceptable carrier, wherein the peptide is up to 20 amino acid residues in length, and has the amino acid sequence selected from the group consisting of SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 64, SEO ID NO: 81, SEG ID NO: 106 and SEQ ID NO: 107.
KLH carrier coupling
The peptide is coupled to a pharmaceutically acceptable carrier, specifically keyhole limpet hemocyanin (KLH).
Covalently bonded peptide-carrier conjugate
A peptide is administered/provided as a conjugate with a pharmaceutically acceptable carrier, where the peptide is covalently bonded to the carrier.
NHS-poly(ethylene oxide) linker
A peptide is provided as a conjugate with a pharmaceutically acceptable carrier, where the peptide is linked to the carrier using an NHS-poly(ethylene oxide) linker.
Vaccine composition including the peptide-carrier conjugate
A vaccine composition is provided that includes the peptide coupled to a pharmaceutically acceptable carrier.
Vaccine composition with adjuvant
The vaccine composition includes an adjuvant.
Overall, the claim set covers a short peptide up to 20 residues conjugated to a pharmaceutically acceptable carrier using specified peptide sequences, with refinements specifying KLH, covalent coupling, an NHS-poly(ethylene oxide) linker, and a vaccine composition optionally including an adjuvant.
Stated Advantages
The mimotope peptides elicit antibodies that bind alpha-synuclein while showing reduced or limited cross-reactivity with beta-synuclein.
Documented Applications
Synucleinopathy treatment using vaccine compositions.
Detection of alpha-syn positive inclusions in transgenic mouse brain sections expressing human alpha-synuclein.
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