Coagulation factor viii with reduced immunogenicity
AssigneeImnate Sarl
InventorJean-Marie Saint-Remy
Life of this patent
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Abstract
The invention describes factor VIII molecules with reduced capacity to elicit activation of NKT cells for use in the treatment of congenital and/or acquired haemophilia A and in bleeding disorders. Said factor VIII molecule is obtainable by: a. identification of at least one NKT cell epitope wherein said epitope comprises hydrophobic aminoacid residues in position P1 and/or P7 b. modification of said epitope(s) by eliminating at least one hydrophobic aminoacid residues in position P1 and/or P7, substituting at least one hydrophobic aminoacid residue in position P1 and/or P7 with a non-hydrophobic residue, or adding a non-hydrophobic residue in position P1 and/or P7.
Claims23
A factor VIII molecule with a domain structure A1-a1-A2-a2-B-a3-A3-C1-C2, in which A1, A2, B, A3, C1 and C2 are domains and a1, a2 and a3 are acidic regions linking said domains;
- wherein the factor VIII molecule has a reduced capacity to activate NKT cells and is obtained by:
- a. identifying at least one NKT cell epitope in a factor VIII molecule, wherein said epitope comprises a seven amino acid residue sequence (positions P1-P7) with a hydrophobic amino acid residue at position P1 and/or P7;
- b. modifying at least one identified NKT cell epitope by deleting at least one hydrophobic amino acid residue in position P1 and/or P7, substituting at least one hydrophobic amino acid residue in position P1 and/or P7 with a non-hydrophobic residue, or adding a non-hydrophobic amino acid residue in position P1 and/or P7.
(canceled)
(canceled)
A method for preparing a factor VIII molecule with reduced capacity to activate NKT cells, the method comprising:
- a. identifying at least one NKT cell epitope in a factor VIII molecule, wherein said epitope comprises a seven amino acid residue sequence (positions P1-P7) with a hydrophobic amino acid residue at position P1 and/or P7;
- b. modifying at least one identified NKT cell epitope by deleting at least one hydrophobic amino acid residue in position P1 and/or P7, substituting at least one hydrophobic amino acid residue in position P1 and/or P7 with a non-hydrophobic amino acid residue, or adding a non-hydrophobic amino acid residue in position P1 and/or P7.
-22. (canceled)
A factor VIII molecule with a domain structure A1-a1-A2-a2-B-a3-A3-C1-C2, in which A1, A2, B, A3, C1 and C2 are domains and a1, a2 and a3 are acidic regions linking said domains;
- wherein the factor VIII molecule comprises at least one modified NKT cell epitope comprising a seven amino acid residue sequence (positions P1-P7) of the formula
- [FWTHY]-X2X3-[ILMV]-X5X6-[FWTHY];
- wherein
- X2, X3, X5, and X6 can be any amino acid;
- and the hydrophobic F, W, T, H, or Y amino acid residue at P1 and/or P7 is replaced with a non-hydrophobic amino acid residue.
Dependencies are inferred from the claim text.