Vaccine engineering
AssigneeAC Immune SA
InventorsDavid Hickman, Maria Pilar Lopez-Deber, Andreas Muhs
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Abstract
The method and constructs disclosed and claimed herein allow to control peptide conformation by modulation of the peptide lipidation pattern, spacer and liposome composition, or via co-administration with small molecules. Accordingly, this technology can be applied to the rational design of liposomal vaccines and for the generation of safer and more efficacious therapies for a range of human disease, in particular those based on misfolded proteins.
Claims18
A method of preparing a modulated immunogenic construct for generating an immune response in an animal or a human, wherein said immunogenic construct comprises a peptide molecule and a hydrophobic moiety covalently bound to the C- and/or N-terminal part of the peptide molecule, which peptide molecule is anchored into the lipid membrane of a liposomal carrier via said hydrophobic moiety, said method comprising:
- a. modulating the secondary and/or quaternary structure and the extent of β-sheet structure and/or β-sheet aggregation of the liposome-bound peptide molecule, comprising one or more of;
- i. modulating the amount of metal ions capable of disrupting peptide-liposome or peptide-peptide stabilizing interactions in the liposomal solution or composition,
- ii. changing the net surface potential of the liposome by modulating the proportion of anionic or cationic lipids in the lipid bilayer of the liposome,
- iii. varying the total number of hydrophobic moieties covalently bound to the N- and/or C-terminus of the peptide molecule such that there is a disparity in the number of hydrophobic moieties between the N- and the C-terminus, and
- iv. adding small molecules to a liposomal solution or composition which are capable of either disaggregating β-sheet structures or promoting aggregation to form β-sheet structures, and
- b. determining the extent of β-sheet structure and/or β-sheet aggregation of the liposome-bound antigenic peptide;
- and
- c. obtaining the modulated immunogenic construct,
- wherein the peptide molecule is a peptide derived from an amyloid protein, a tau protein, a prion protein, an alpha-synuclein protein, or a huntington protein.
A method of modulating the secondary and/or quaternary structure of an antigenic peptide molecule, which antigenic peptide molecule has a hydrophobic moiety covalently bound to its C- and/or N-terminus and is anchored into the lipid membrane of a liposomal carrier via said hydrophobic moiety, comprising
- a. modulating the amount of metal ions capable of disrupting peptide-liposome or peptide-peptide stabilizing interactions in the liposomal solution or composition;
- and/or
- b. changing the net surface potential of the liposome by modulating the proportion of anionic or cationic lipids in the lipid bilayer of the liposome;
- and/or
- c. varying the total number of hydrophobic moieties covalently bound to the N- and/or C-terminus of the peptide molecule such that there is a disparity in the number of hydrophobic moieties between the N- and the C-terminus;
- and/or
- d. adding small molecules to a liposomal solution or composition which are capable of either disaggregating β-sheet structures or promoting aggregation to form β-sheet structures,
- wherein said modulation of the secondary and/or quaternary structure leads to an increase or decrease of the extent of β-sheet structures and/or β-sheet aggregation of the liposome-bound antigenic peptide molecule, and
- wherein the antigenic peptide molecule is a peptide derived from an amyloid protein, a tau protein, a prion protein, an alpha-synuclein protein, or a huntington protein.
An immunogenic construct comprising a peptide molecule anchored into the membrane of a liposome via hydrophobic moieties covalently bound to the N-terminus, C-terminus, or both of the peptide molecule such that there is a disparity between the number of hydrophobic moieties between the N-terminus and C-terminus, or a composition comprising said immunogenic construct,
- wherein said immunogenic construct is modulated to have an increased extent of β-sheet structure and/or β-sheet aggregation of between 50%-100%, as compared prior to modulation,
- wherein the number of hydrophobic moieties covalently bound to the N-terminus of the peptide molecule exceeds the number of hydrophobic moieties covalently bound to the C-terminus of the peptide molecule by at least three, or by at least four moieties, or the number of hydrophobic moieties covalently bound to the C-terminus of the peptide molecule exceeds the number of hydrophobic moieties covalently bound to the N-terminus of the peptide molecule by at least three, or by at least four moieties, and
- wherein the peptide molecule is a peptide derived from an amyloid protein, a tau protein, a prion protein, an alpha synuclein protein, or a huntingtin protein.
An immunogenic construct comprising a peptide molecule anchored into the membrane of a liposome via a hydrophobic moiety or a composition comprising said immunogenic construct, wherein the hydrophobic moiety is covalently bound to the C-terminal, N-terminal, or both the C-terminal and N-terminal part of the peptide molecule, and wherein the immunogenic construct is modulated to show an reduced extent of β-sheet aggregation and comprises at least two features selected from the group consisting of:
- i. a net negative surface potential of the liposome of at least >0mV, of at least >+10 mV, or of at least >+35 mV, in PBS;
- ii. a length of the individual hydrophobic anchor molecule of less than 4 carbon atoms, particularly less than 3 carbon atoms, particularly less than 2 carbon atoms;
- iii. a number of hydrophobic anchor molecules at one end of the peptide molecule totalling 1 anchor molecule;
- and
- iv. presence of Cu(II) and/or Zn(II) metal ions and/or small molecules capable of disaggregating β-sheet aggregates,
- wherein the peptide molecule is a peptide derived from an amyloid protein, a tau protein, a prion protein, an alpha-synuclein protein, or huntingtin protein.
Dependencies are inferred from the claim text.