NOVEL IMMUNOTHERAPY AGAINST NEURONAL AND BRAIN TUMORS

• US 20090123489A1
• Filed: 07/25/2008
• Published: 05/14/2009
• Est. Priority Date: 07/27/2007
• Status: Active Grant

• Current Assignee: Immatics Biotechnologies GmbH (Immatics NV)
• Original Assignee: Immatics Biotechnologies GmbH (Immatics NV)
• Inventors: Schoor, Oliver, Walter, Steffen, Trautwein, Claudia, WEINSCHENK, Toni, Hilf, Norbert, Singh, Harpreet
• Granted Patent: US 9,175,040 B2
• Time in Patent Office: Days
• US Class Current: 424/185.100
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-cells
• CPC Class Codes: A61K 2039/572 cytotoxic response
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4644 Cancer antigens
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 14/4748 Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
• CPC Class Codes: C07K 14/495 Transforming growth factor [TGF]
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 19/00 Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 : having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C12N 2502/1157 : Monocytes, macrophages
• CPC Class Codes: C12N 5/0636 : T lymphocytes
• CPC Class Codes: C12N 5/0638 : Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
• CPC Class Codes: C12N 9/0036 : acting on NADH or NADPH (1.6)
• CPC Class Codes: C12N 9/13 : transferring sulfur containing groups (2.8)
• CPC Class Codes: C12Y 208/02011 : Galactosylceramide sulfotransferase (2.8.2.11)

Abstract

The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to 11 novel peptide sequences and their variants derived from HLA class I and class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses.

Claims

1. A peptide comprising a sequence that is selected from the group of SEQ ID NO:

1 to SEQ ID NO;

11 wherein the peptide is capable of inducing T cells cross-reacting with the peptide.

8. The peptide of claim 1, wherein the amino acid sequence comprises SEQ ID NO:

3.

9. A variant of the peptide of claim 8 wherein the variant binds to a MHC class I molecule HLA A*02 allele and wherein the variant is capable of stimulating CD8 cells, and wherein the variant has the following motif X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, wherein

X₁ is A, I, L, F, K, M, Y or V;

X₂ is I, M, or L;

X₃ is I, A, Y, F, P, M, S or R;

X₄ is D, E, G, P or T;

X₅ is G, I, K, Y, N, F or V;

X₆ is V, I, L or T;

X₇ is E, A, Y or H;

X₈ is S, K or E; and

X₉ is V or L.

10. The peptide of claim 1, wherein the amino acid sequence comprises SEQ ID NO:

4.

11. A variant of the peptide of claim 10 wherein the variant binds to a MHC class I molecule HLA A*02 allele and wherein the variant is capable of stimulating CD8 cells, and wherein the variant has the following motif X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, wherein

X₁ is F, I, L, K, M, Y or V;

X₂ is L or M;

X₃ is L, A, Y, F, P, M, S or R;

X₄ is P, E, G, D, T or K;

X₅ is D, I, K, Y, N, G, F, V or H;

X₆ is T, I or L;

X₇ is D, A, Y or H;

X₈ is G, K, E or S; and

X₉ is L.

12. The peptide of claim 1, wherein the amino acid sequence comprises SEQ ID NO:

5.

13. A variant of the peptide of claim 12 wherein the variant binds to a MHC class I molecule HLA A*02 allele and wherein the variant is capable of stimulating CD8 cells, and wherein the variant has the following motif X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, wherein

X₁ is K, I, L, F, M or Y;

X₂ is V, M or L;

X₃ is F, A, Y, P, M or S;

X₄ is A, E, G, P or T;

X₅ is G, I, K, Y, N, F or V;

X₆ is I, L or T;

X₇ is P, A, Y or H;

X₈ is T, K, or E; and

X₉ is V or L.

14. The peptide of claim 1, wherein the amino acid sequence comprises SEQ ID NO:

6.

15. A variant of the peptide of claim 14 wherein the variant binds to a MHC class I molecule HLA A*02 allele and wherein the variant is capable of stimulating CD8 cells, and wherein the variant has the following motif X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, wherein

X₁ is Q, V or Y;

X₂ is Q;

X₃ is S, P, F, I or M;

X₄ is D, E, K, N or P;

X₅ is Y, V, L or I;

X₆ is S, I, V, L or A;

X₇ is A, H or V;

X₈ is A or Y; and

X₉ is L.

16. The peptide of claim 1, wherein the amino acid sequence comprises SEQ ID NO:

7.

17. A variant of the peptide of claim 16 wherein the variant binds to a MHC class I molecule HLA A*02 allele and wherein the variant is capable of stimulating CD8 cells, and wherein the variant has the following motif X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, wherein X₁ is T, V or Y;

X₂ is Q;

X₃ is D, P, F, I or M;

X₄ is D, E, K, N or P;

X₅ is Y, V, L or I;

X₆ is V, I, L or A;

X₇ is L, H or V;

X₈ is E or Y; and

X₉ is V or L.

18. The peptide of claim 1, wherein the amino acid sequence comprises SEQ ID NO:

8.

19. A variant of the peptide of claim 18 wherein the variant binds to a MHC class I molecule HLA B*38 allele and wherein the variant is capable of stimulating CD8 cells, and wherein the variant has the following motif X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, wherein X₁ is Q or I;

X₂ is H;

X₃ is E or D;

X₄ is G, E, P, L, K or S;

X₅ is T, M, V, A, R, N or H;

X₆ is V, I, T or K;

X₇ is N, Y, V or N;

X₈ is I, K, Y, N or R; and

X₉ is F.

20. A peptide according to claim 1, wherein the peptide has an overall length of between 8 and 16 amino acids.

21. The peptide according to claim 1, wherein the peptide consists essentially of an amino acid sequence according to SEQ ID NO:

1 to SEQ ID NO;

11.

22. The peptide according to claim 1, wherein the peptide consists essentially of an amino acid sequence according to SEQ ID NO:

1 to SEQ ID NO;

11.

23. The peptide according to claim 1, wherein the peptide is modified or includes non-peptide bonds.

24. The peptide according to claim 1, wherein the peptide is a fusion protein, comprising N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii).

25. A nucleic acid, encoding a peptide according to claim 1.

26. The nucleic acid according to claim 25 which is DNA, cDNA, PNA, CNA, RNA or combinations thereof.

27. An expression vector capable of expressing a nucleic acid according to claim 25.

28. A peptide according to claim 1 for use in medicine.

29. A host cell comprising a nucleic acid according to claim 25.

30. The host cell according to claim 29, wherein the host cell is an antigen presenting cell or a dendritic cell.

31. A method of producing a peptide according to claim 1, the method comprising culturing the host cell according to claim 30 and isolating the peptide from the host cell or its culture medium.

32. An in vitro method for producing activated cytotoxic T lymphocytes (CTL), the method comprising contacting in vitro CTL with antigen loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate the CTL in an antigen specific manner, wherein the antigen is a peptide according to claim 1.

33. The method according to claim 32, wherein the antigen is loaded onto class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell or precursors thereof.

34. The method according to claim 32, wherein the antigen-presenting cell comprises an expression vector capable of expressing the peptide comprising SEQ ID NO:

1 to SEQ ID NO;

11.

35. Activated cytotoxic T lymphocytes (CTL), produced by the method according to claim 32, which selectively recognize a cell aberrantly expressing a polypeptide comprising an amino acid sequence of SEQ ID NO:

1 to SEQ ID NO;

11.

36. A method of killing target cells in a patient, wherein the target cells aberrantly express a polypeptide of claim 1, the method comprising administering to the patient an effective number of cytotoxic T lymphocytes (CTL) as defined in claim 35.

37. Use of a peptide according to claim 1 as a medicament or in the manufacture of a medicament.

38. Use according to claim 37, wherein the medicament is a vaccine.

39. Use according to claim 37, wherein the medicament is active against cancer.

40. Use according to claim 39, wherein the cancer cells are astrocytoma, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor, oligodendrogliomas, ependymoma, glioblastoma multiforme, mixed gliomas, oligoastrocytomas, medulloblastoma, retinoblastoma, neuroblastoma, germinoma, teratoma, gangliogliomas, gangliocytoma, central gangliocytoma, primitive neuroectodermal tumors (PNET, e.g. medulloblastoma, medulloepithelioma, neuroblastoma, retinoblastoma, ependymoblastoma), tumors of the pineal parenchyma (e.g. pineocytoma, pineoblastoma), ependymal cell tumors, choroid plexus tumors, neuroepithelial tumors of uncertain origin (e.g. gliomatosis cerebri, astroblastoma) or glioblastoma cells.

2. A peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:

1 to SEQ ID NO;

11, wherein the peptide maintains the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or -II and wherein the peptide is capable of stimulating CD4 or CD8 T cells.

3. A peptide of claim 2 wherein the sequence is at least 80% homologous to the sequence set forth in SEQ D NO:

1 to SEQ ID NO;

11 and maintains the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or -II, and wherein the peptide is capable of stimulating CD4 or CD8 T cells.

4. The peptide of claim 2 wherein the amino acid sequence comprises SEQ ID NO:

1.

5. A variant of the peptide of claim 4 wherein the variant binds to a MHC class I molecule HLA A*0205 allele and wherein the variant is capable of stimulating CD8 cells, and wherein the variant has the following motif X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, wherein

X₁ is A, V, or Y;

X₂ is L;

X₃ is T, P, F, I or M;

X₄ is T, E, D, K or N;

X₅ is L, V, L or I;

X₆ is M, I, V, L, I or A;

X₇ is H or V;

X₈ is Q or Y; and

X₉ is L.

6. The peptide of claim 2 wherein the amino acid sequence comprises SEQ ID NO:

2.

7. A variant of the peptide of claim 6 wherein the variant binds to a MHC class I molecule HLA A*02 allele and wherein the variant is capable of stimulating CD8 cells, and wherein the variant has the following motif X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, wherein

X₁ is F, I, L, K, M, Y or V;

X₂ is L or M;

X₃ is Y, A, F, P, M, S or R;

X₄ is K, E, G, P, D or T;

X₅ is V, I, K, Y, N, G, F or H;

X₆ is I, L, or T;

X₇ is L, A, Y, or H;

X₈ is S, K, E, or S; and

X₉ is L.