Modulation of antigen immunogenicity by deleting epitopes recognized by NKT cells
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Publication Number
US-9732118-B2
Publication Date
2017-08-15
Expiration Date
Abstract
The invention describes a method and compounds for the prevention of immune responses towards allofactors, towards viral vectors used for gene therapy and gene vaccination, towards proteins to which subjects are naturally exposed, towards genetically-modified organisms and towards undesirable effects related to vaccine administration for allergic or infectious diseases.
Core Innovation
The invention relates to reducing NKT cell activation towards a peptide or a polypeptide in a mammal by administering an isolated peptide or polypeptide. The isolated peptide or polypeptide is produced by identifying at least one NKT epitope in an isolated peptide having the sequence of the peptide or polypeptide, and then eliminating the NKT cell epitope by deleting and/or substituting hydrophobic amino acid residue(s) at position P1 or P7 of the epitope.
The eliminated epitope is defined in relation to an epitope pattern comprising [F/W/T/H/Y]-X2X3-[I/L/M/V]-X5X6-[F/W/T/H/Y], wherein X stands for any amino acid. The modification is positioned to reduce CD1d-mediated NKT activation by deleting at least one hydrophobic amino acid residue in position P1 or P7, or both, or substituting at least one hydrophobic amino acid residue in position P1 or P7, or both, with a non-hydrophobic residue.
The approach is described as a strategy to reduce antigen immunogenicity by deleting or substituting CD1d-binding motifs in peptides/polypeptides that can be presented to NKT cells. Hydrophobic residues at CD1d-anchoring positions P1 and/or P7 enable CD1d presentation and NKT activation, which is associated with cytokine release and can suppress adaptive CD4+ T-cell responses. The modified peptides/polypeptides are positioned as medicaments to prevent immune responses toward allofactors, therapeutic proteins, viral vectors, genetically modified organisms/food proteins, allergens, and vaccines.
Claims Coverage
The partial claim set contains one independent claim. The independent claim covers a method that reduces NKT cell activation toward a peptide or polypeptide by identifying NKT epitopes and eliminating them through deletion and/or substitution of hydrophobic residues at positions P1 and P7, constrained by an epitope pattern.
Reducing NKT cell activation by epitope elimination at P1/P7
A method of reducing NKT cell activation towards a peptide or a polypeptide in a mammal by administering an isolated peptide or polypeptide produced by identifying at least one NKT epitope and eliminating said NKT cell epitope by deleting at least one hydrophobic amino acid residue in position P1 or P7, or both, or substituting at least one hydrophobic amino acid residue in position P1 or P7, or both, with a non-hydrophobic residue, wherein the NKT cell epitope comprises [F/W/T/H/Y]-X2X3-[I/L/M/V]-X5X6-[F/W/T/H/Y].
Epitope identification using NKT activation or CD1d binding capacity
The method wherein identifying at least one NKT epitope comprises incubating the peptide or polypeptide with CD1d-carrying cells plus a population of NKT cells and determining NKT-cell activation, or determining the peptide or polypeptide’s capacity to bind to the CD1d molecule.
Overall, the claims focus on reducing NKT cell activation by eliminating NKT epitopes through deleting and/or substituting hydrophobic residues at CD1d-anchoring positions P1 and/or P7 within a defined epitope pattern, with epitope identification supported by either NKT-cell activation with CD1d-carrying cells or measurement of CD1d binding capacity.
Stated Advantages
Reduces NKT cell activation towards a peptide or polypeptide in a mammal.
Reduces antigen immunogenicity by eliminating CD1d-binding motifs in peptides/polypeptides presented to NKT cells.
Elimination of the modified epitopes is described as abrogating CD1d tetramer binding and NKT activation, and reducing antibody formation and neutralizing antibody levels in the provided examples.
Documented Applications
Medicaments to prevent immune responses toward allofactors.
Medicaments to prevent immune responses toward therapeutic proteins, including factor VIII (FVIII) in hemophilia A mice as described in the provided content.
Medicaments to prevent immune responses toward viral vectors, including an adenovirus serotype 5 (Ad5) hexon context as described in the provided content.
Medicaments to prevent immune responses toward genetically modified organisms/food proteins as described in the provided content.
Medicaments to prevent immune responses toward allergens, including Mal d 1 and alpha-gliadin, and Der p 1 as described in the provided content.
Medicaments to prevent immune responses toward vaccines as described in the provided content.
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