Identification of Tumor-Associated Antigens for Diagnosis and Therapy

• US 20110189179A1
• Filed: 04/13/2011
• Published: 08/04/2011
• Est. Priority Date: 09/12/2005
• Status: Active Grant

• Current Assignee: Astellas Pharma Incorporated, TRANSLATIONALE ONKOLOGIE AN DER UNIVERSITATSMEDIZIN DER JOHANNES GUTENBERG-UNIVERSITAT MAINZ GEMEINNUTZIGE GMBH
• Original Assignee: Ganymed Pharmaceuticals AG (Astellas Pharma Incorporated), Johannes Gutenberg-Universitã¤T Mainz
• Inventors: Usener, Dirk, Türeci, Özlzem, Sahin, Ugur, Koslowski, Michael
• Granted Patent: US 8,975,375 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/57 characterised by the type of response, e.g. Th1, Th2
• CPC Class Codes: A61K 2039/572 cytotoxic response
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/4748 Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/30 from tumour cells
• 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: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 33/574 for cancer

Abstract

The invention relates to genetic products the expression of which is associated with cancer diseases. The invention also relates to the therapy and diagnosis of diseases in which the genetic products are expressed or aberrantly expressed, in particular cancer diseases.

Claims

1. A pharmaceutical composition, comprising an agent which

(I) inhibits expression or activity of a tumor-associated antigen and/or

(II) has tumor-inhibiting activity, and is selective for cells expressing or abnormally expressing a tumor-associated antigen and/or

(III) when administered, selectively increases the amount of complexes between an MHC molecule and a tumor-associated antigen or a part thereof, the tumor-associated antigen having a sequence encoded by a nucleic acid which is selected from the group consisting of:

(a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs;

1, 5, 9, 13, 17, 21, 25, 28, 30, 35, 39, 41, 45, 49, 61, 62, and 64-67, a part or derivative thereof,

(b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions,

(c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and

(d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c).

2. The pharmaceutical composition as claimed in claim 1, wherein the agent under (II) causes induction of cell death, reduction in cell growth, damage to the cell membrane or secretion of cytokines.

3. The pharmaceutical composition as claimed in claim 1, wherein the agent under (I) or (II) is an antisense nucleic acid which hybridizes selectively with the nucleic acid coding for the tumor-associated antigen.

4. The pharmaceutical composition as claimed in claim 1, wherein the agent under (I) or (II) is an antibody which binds selectively to the tumor-associated antigen.

5. The pharmaceutical composition as claimed in claim 1, wherein the agent comprises one or more components selected from the group consisting of:

(i) the tumor-associated antigen or a part thereof,

(ii) a nucleic acid which codes for the tumor-associated antigen or a part thereof,

(iii) an antibody which binds to the tumor-associated antigen or a part thereof,

(iv) an antisense nucleic acid which hybridizes specifically with a nucleic acid coding for the tumor-associated antigen,

(v) an siRNA directed against a nucleic acid coding for the tumor-associated antigen,

(vi) a host cell which expresses the tumor-associated antigen or a part thereof, and

(vii) isolated complexes between the tumor-associated antigen or a part thereof and an MHC molecule.

6. The pharmaceutical composition as claimed in claim 1, wherein the agent comprises two or more agents which in each case selectively inhibit expression or activity of different tumor-associated antigens, which are in each case selective for cells expressing or abnormally expressing different tumor-associated antigens or which increase the amount of complexes between MHC molecules and different tumor-associated antigens or parts thereof, with at least one of the tumor-associated antigens having a sequence encoded by a nucleic acid which is selected from the group consisting of:

(a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs;

1, 5, 9, 13, 17, 21, 25, 28, 30, 35, 39, 41, 45, 49, 61, 62, and 64-67, a part or derivative thereof,

(b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions,

(c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and

(d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c).

16. The pharmaceutical composition as claimed in claim 1 or 7, which may be used for the treatment or prevention of cancer.

17. The pharmaceutical composition as claimed in claim 16, wherein the cancer is a lung tumor, a breast tumor, a prostate tumor, a melanoma, a colon tumor, a gastric tumor, a pancreatic tumor, an ENT tumor, a renal cell carcinoma or a cervical carcinoma, a colon carcinoma or a mammary carcinoma.

18. The pharmaceutical composition as claimed in claim 1 or 7, wherein the tumor-associated antigen comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

2, 6, 10, 14, 18, 22, 26, 29, 31, 36, 40, 42, 46, 50-60, 63, 68, and 69, a part thereof, or derivative thereof.

19. The pharmaceutical composition as claimed in claim 1 or 7, which is in the form of a vaccine.

20. The pharmaceutical composition as claimed in claim 19 for therapeutic use, prophylactic use, or combinations thereof.

31. A method of treating or preventing a disease characterized by expression or abnormal expression of a tumor-associated antigen, which method comprises the step of administration of a pharmaceutical composition as claimed in claim 1 or 7, the tumor-associated antigen having a sequence encoded by a nucleic acid which is selected from the group consisting of:

(a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs;

1, 5, 9, 13, 17, 21, 25, 28, 30, 35, 39, 41, 45, 49, 61, 62, and 64-67, a part or derivative thereof,

(b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions,

(c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and

(d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c).

37. A method of inhibiting the development of cancer in a patient, wherein the method comprises the step of administering an effective amount of a pharmaceutical composition as claimed in claim 1 or 7.

7. A pharmaceutical composition, comprising one or more components selected from the group consisting of:

(i) a tumor-associated antigen or a part thereof,

(ii) a nucleic acid which codes for a tumor-associated antigen or a part thereof,

(iii) an antibody which binds to a tumor-associated antigen or a part thereof,

(iv) an antisense nucleic acid which hybridizes specifically with a nucleic acid coding for a tumor-associated antigen,

(v) an siRNA directed against a nucleic acid coding for a tumor-associated antigen,

(vi) a host cell which expresses a tumor-associated antigen or a part thereof, and

(vii) isolated complexes between a tumor-associated antigen or a part thereof and an MHC molecule, the tumor-associated antigen having a sequence encoded by a nucleic acid which is selected from the group consisting of;

(a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs;

1, 5, 9, 13, 17, 21, 25, 28, 30, 35, 39, 41, 45, 49, 61, 62, and 64-67, a part or derivative thereof,

(b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions,

(c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and

(d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c).

8. The pharmaceutical composition as claimed in claim 7, wherein the nucleic acid of (ii) is present in an expression vector.

9. The pharmaceutical composition as claimed in claim 7, wherein the host cell secretes the tumor-associated antigen or the part thereof.

10. The pharmaceutical composition as claimed in claim 7, wherein the host cell additionally expresses an MHC molecule which binds to the tumor-associated antigen or the part thereof.

11. The pharmaceutical composition as claimed in claim 10, wherein the host cell expresses the MHC molecule and/or the tumor-associated antigen or the part thereof in a recombinant manner.

12. The pharmaceutical composition as claimed in claim 10, wherein the host cell expresses the MHC molecule endogenously.

13. The pharmaceutical composition as claimed in claim 7, wherein the host cell is an antigen-presenting cell.

14. The pharmaceutical composition as claimed in claim 7, wherein the antibody is a monoclonal, chimeric or humanized antibody, or is a fragment of an antibody.

15. The pharmaceutical composition as claimed in claim 7 or 14 wherein the antibody is coupled to a therapeutic or diagnostic agent.

21. A method of diagnosing or monitoring a disease characterized by expression or abnormal expression of a tumor-associated antigen, wherein the method comprises the step of detecting or determining the amount of:

(i) of a nucleic acid which encodes for the tumor-associated antigen or of a part thereof, or

(ii) of the tumor-associated antigen or of a part thereof, or

(iii) of an antibody to the tumor-associated antigen or a part thereof or

(iv) of T lymphocytes which are specific to the tumor-associated antigen or to a part thereof in a biological sample isolated from a patient, with the tumor-associated antigen having a sequence encoded by a nucleic acid which is selected from the group consisting of;

(a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs;

1, 5, 9, 13, 17, 21, 25, 28, 30, 35, 39, 41, 45, 49, 61, 62, and 64-67, a part or derivative thereof,

(b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions,

(c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and

(d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c);

or

(v) combinations of (i), (ii), (iii), or (iv).

22. The method as claimed in claim 21, wherein the detection or determination of the amount comprises:

(i) contacting the biological sample with an agent which binds specifically to the nucleic acid coding for the tumor-associated antigen or to the part thereof, to the tumor-associated antigen or the part thereof, to the antibody or to the T lymphocytes, and

(ii) detecting the formation of or determining the amount of a complex between the agent and the nucleic acid or the part thereof, the tumor-associated antigen or the part thereof, the antibody or the T lymphocytes.

23. The method as claimed in claim 22, wherein the agent which binds specifically to the nucleic acid coding for the tumor-associated antigen or to the part thereof is an oligonucleotide or polynucleotide, which hybridizes specifically to the nucleic acid or to the part thereof.

24. The method as claimed in claim 22, wherein the agent which binds specifically to the tumor-associated antigen or the part thereof is an antibody binding specifically to the tumor-associated antigen or to the part thereof.

25. The method as claimed in claim 22, wherein the agent which binds specifically to the antibody is a protein or peptide binding specifically to the antibody.

26. The method as claimed in claim 22, wherein the agent which binds specifically to the T lymphocytes is a cell presenting the complex between the tumor-associated antigen or the part thereof and an MHC molecule.

27. The method as claimed in claim 21 wherein the monitoring of the disease comprises determining regression, course or onset of the disease in a sample from a patient who has the disease or is suspected of falling ill with the disease.

28. The method as claimed in claim 27, which comprises a detection or determination of the amount in a first sample at a first point in time and in a further sample at a second point in time and a comparison of the two samples.

29. The method as claimed in claim 22, wherein the agent is labeled in a detectable manner.

30. The method as claimed in claim 21, in which the sample comprises body fluid and/or body tissue.

33. The method as claimed in claim 24 or 32, wherein the antibody is a monoclonal, chimeric or humanized antibody, or is a fragment of an antibody.

38. The method as claimed in claim 21, or 32, in which the tumor-associated antigen comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

2, 6, 10, 14, 18, 22, 26, 29, 31, 36, 40, 42, 46, 50-60, 63, 68, and 69, a part or derivative thereof.

32. A method of treating, preventing, diagnosing or monitoring a disease characterized by expression or abnormal expression of a tumor-associated antigen, wherein the method comprises the step of administering an antibody binding to the tumor-associated antigen or to a part thereof and coupled to a therapeutic or diagnostic agent, the tumor-associated antigen having a sequence encoded by a nucleic acid which is selected from the group consisting of:

(a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs;

1, 5, 9, 13, 17, 21, 25, 28, 30, 35, 39, 41, 45, 49, 61, 62, and 64-67, a part or derivative thereof,

(b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions,

(c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and

(d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c).

34. A method of treating a patient having a disease characterized by expression or abnormal expression of a tumor-associated antigen, wherein the method comprises the steps of:

(i) providing a sample containing immunoreactive cells,

(ii) contacting the sample with a host cell expressing the tumor-associated antigen or a part thereof, under conditions which favor production of cytolytic or cytokine-releasing T cells against the tumor-associated antigen or the part thereof, and

(iii) introducing the cytolytic or cytokine-releasing T cells into the patient in an amount suitable for lysing cells expressing the tumor-associated antigen or a part thereof, the tumor-associated antigen having a sequence encoded by a nucleic acid which is selected from the group consisting of;

(a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs;

1, 5, 9, 13, 17, 21, 25, 28, 30, 35, 39, 41, 45, 49, 61, 62, and 64-67, a part or derivative thereof,

(b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions,

(c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and

(d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c).

35. The method as claimed in claim 34, wherein the host cell recombinantly expresses an MHC molecule binding to the tumor-associated antigen or to a part thereof.

36. The method as claimed in claim 34, wherein the host cell endogenously expresses an MHC molecule binding to the tumor-associated antigen or to a part thereof.

49. The method as claimed in claim 36, in which the tumor-associated antigen comprises an amino acid sequence selected from the group consisting of:

SEQ ID NOs;

2, 6, 10, 14, 18, 22, 26, 29, 31, 36, 40, 42, 46, 50-60, 63, 68, and 69, and a part or derivative thereof.

39. An agent, which binds specifically to a protein or polypeptide or to a part thereof, the protein or polypeptide being encoded by a nucleic acid selected from the group consisting of:

(a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs;

1, 5, 9, 13, 17, 21, 25, 28, 30, 35, 39, 41, 45, 49, 61, 62, and 64-67, a part or derivative thereof,

(b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions,

(c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and

(d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c).

40. The agent as claimed in claim 39, in which the protein or polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

2, 6, 10, 14, 18, 22, 26, 29, 31, 36, 40, 42, 46, 50-60, 63, 68, and 69, and a part or derivative thereof.

41. The agent as claimed in claim 39, which is an antibody.

42. The agent as claimed in claim 41, in which the antibody is a monoclonal, chimeric or humanized antibody, or is a fragment of an antibody.

46. A conjugate between an agent as claimed in any of claims 39-42 and a therapeutic or diagnostic agent.

47. The conjugate as claimed in claim 46, in which the therapeutic or diagnostic agent is a toxin.

43. An antibody, which binds selectively to a complex of:

(i) a protein or polypeptide or a part thereof, and

(ii) an MHC molecule to which the protein or polypeptide or the part thereof binds, with the antibody not binding to (i) or (ii) alone and the protein or polypeptide being encoded by a nucleic acid selected from the group consisting of;

(a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs;

1, 5, 9, 13, 17, 21, 25, 28, 30, 35, 39, 41, 45, 49, 61, 62, and 64-67, a part or derivative thereof,

(b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions,

(c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and

(d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c).

44. The antibody as claimed in claim 43, in which the protein or polypeptide comprises an amino acid sequence selected from the group consisting of:

SEQ ID NOs;

2, 6, 10, 14, 18, 22, 26, 29, 31, 36, 40, 42, 46, 50-60, 63, 68, and 69, and a part or derivative thereof.

45. The antibody as claimed in claim 43, which is a monoclonal, chimeric or humanized antibody, or is a fragment of an antibody.

50. A conjugate between an antibody as claimed in any of claims 43-45 and a therapeutic or diagnostic agent.

48. A kit for detecting expression or abnormal expression of a tumor-associated antigen, wherein the kit comprises agents for detecting or determining the amount

(i) of a nucleic acid which codes for the tumor-associated antigen or of a part thereof, and/or

(ii) of the tumor-associated antigen or of a part thereof, and/or

(iii) of antibodies which bind to the tumor-associated antigen or to a part thereof, and/or

(iv) of T cells which are specific for a complex between the tumor-associated antigen or a part thereof and an MHC molecule, the tumor-associated antigen having a sequence encoded by a nucleic acid which is selected from the group consisting of:

(a) a nucleic acid which comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs;

1, 5, 9, 13, 17, 21, 25, 28, 30, 35, 39, 41, 45, 49, 61, 62, and 64-67, a part or derivative thereof,

(b) a nucleic acid which hybridizes with the nucleic acid of (a) under stringent conditions,

(c) a nucleic acid which is degenerate with respect to the nucleic acid of (a) or (b), and

(d) a nucleic acid which is complementary to the nucleic acid of (a), (b) or (c).