HPV epitopes targeted by T cells infiltrating cervical malignancies for use in vaccines
The present invention relates to novel CD4+ and CD8+ T cell epitopes that are specific for HPV-specific E6 and E7 oncoproteins, to peptides comprising these novel T cell epitopes, and to (vaccine) compositions comprising these peptides for use in methods for the prevention and/or treatment of HPV related diseases. Preferred epitopes are recognized by a T cell that infiltrates a cervical neoplastic lesion or by a T cell from a draining lymph node, and are presented by an HLA-DQ or HLA-DP molecule, or an HLA-B.
1. An immunogenic pharmaceutical composition comprising:
(a) a peptide having a length of no more than 45 amino acids and comprising at least 31 and no more than 35 contiguous amino acids from the amino acid sequence of an HPV protein, wherein the contiguous amino acid sequence comprises at least one of SEQ ID NOs: 7, 14, 22, 24, 25, or 26; and
(b) an immune-stimulating amount of a pharmaceutically acceptable adjuvant.
2. The immunogenic pharmaceutical composition according to claim 1 , wherein the contiguous amino acid sequence comprises an epitope that is presented by an HLA-B molecule.
3. The immunogenic pharmaceutical composition according to claim 1 , wherein the composition comprises at least two different peptides as defined in claim 1 .
4. The immunogenic pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable adjuvant acts via a Toll-like receptor.
5. The immunogenic pharmaceutical composition according to claim 1 , wherein the composition is for intravenous, subcutaneous, intramuscular, mucosal, intradermal and/or intracutaneous administration.
6. The immunogenic pharmaceutical composition according to claim 1 for the treatment or prevention of an HPV related disease.
7. The immunogenic pharmaceutical composition according to claim 5 , wherein the HPV related disease is selected from the group consisting of: cervical intraepithelial neoplasia of the cervix (CIN), vulva (VIN), vagina (VaIN), anus (AIN), and penis (PIN) and cancer of the cervix, vulva, vagina, anus, penis and head & neck.
8. The immunogenic pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable adjuvant is synthetic.
9. The immunogenic pharmaceutical composition according to claim 4 , wherein the pharmaceutically acceptable adjuvant is selected from the group consisting of: Gram positive bacterial glycolipids, fimbriae, outer membrane proteins, heat shock proteins, mycobacterial lipoarabinomannans, dsRNA, poly(I:C), Gram negative glycolipids, viral coat or envelope proteins, taxol or derivatives thereof, hyaluronan containing oligosaccharides or fibronectins, bacterial flagellae or flagellin, mycobacterial lipoproteins, group B Streptococcus heat labile soluble factor (GBS-F), Staphylococcus modulins, and imidazoquinolines.
10. The immunogenic pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable adjuvant is selected from the group consisting of:
dsRNA, poly(I:C), unmethylated CpG DNA, IC31, IMSAVAC, Montanide ISA-51 and Montanide ISA 720.
11. The immunogenic pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable adjuvant is physically linked to the peptide.
12. The immunogenic pharmaceutical composition according to claim 1 , further comprising at least one immune modulator.
13. The immunogenic pharmaceutical composition according to claim 1 , further comprising at least one additional peptide having a length of no more than 100 amino acids and comprising at least 19 contiguous amino acids from the amino acid sequence of at least one of an HPV E6 and E7 protein, wherein the contiguous amino acid sequence of the additional peptide comprises an epitope that is recognized by a T cell that infiltrates a cervical neoplastic lesion or by a T cell from a draining lymph node.
14. The immunogenic pharmaceutical composition according to claim 13 , wherein the epitope of the additional peptide is selected from the group consisting of SEQ ID NO: 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, and 23.
15. The immunogenic pharmaceutical composition according to claim 1 , wherein the peptide comprises SEQ ID NO: 34.
16. The immunogenic pharmaceutical composition according to claim 1 , wherein the peptide consists of SEQ ID NO: 34.
17. The immunogenic pharmaceutical composition according to claim 1 , wherein the peptide comprises SEQ ID NO: 35.
18. The immunogenic pharmaceutical composition according to claim 1 , wherein the peptide consists of SEQ ID NO: 35.
19. The immunogenic pharmaceutical composition according to claim 1 , wherein the HLA-B molecule is an HLA-B7, HLA-B14, HLA-B27 or HLA-B57 molecule.