Immunogenic peptides and methods of use

• US 9,175,057 B2
• Filed: 02/10/2011
• Issued: 11/03/2015
• Est. Priority Date: 02/24/2006
• Status: Active Grant

• Current Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Original Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Inventors: Schlom, Jeffrey, Tsang, Kwong-Yok, Pastan, Ira H.
• Primary Examiner(s): Reddig, Peter J
• Application Number:
  US13/025,094
• Publication Number:
  US 20110165117A1
• Time in Patent Office: 1,727 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2239/59 Reproductive system, e.g. uterus, ovaries, cervix or testes
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• 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 39/4615 Dendritic cells
• CPC Class Codes: A61K 39/4622 Antigen presenting cells
• CPC Class Codes: A61K 39/464493 Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; Prostatic acid phosphatase [PAP]; Prostate-specific G-protein-coupled receptor [PSGR]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/4748 Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
• CPC Class Codes: C07K 14/82 Translation products from oncogenes
• CPC Class Codes: C12N 2799/023 where the vector is derived from a poxvirus
• CPC Class Codes: C12N 2800/00 Nucleic acids vectors
• CPC Class Codes: G01N 2333/70517 CD8
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The PAGE4 gene is expressed in reproductive tissues, and is expressed in reproductive cancers, such as prostate cancer, uterine cancer, and testicular cancer. Immunogenic PAGE4 polypeptides are disclosed herein, as are nucleic acids encoding the immunogenic PAGE4 polypeptides, vectors including these polynucleotides, and host cells transformed with these vectors. These polypeptides, polynucleotides, vectors, and host cells can be used to induce an immune response to PAGE4. Diagnostic methods to detect PAGE4 are also described.

Claims

1. A method of treating a subject with a PAGE4-expressing cancer, comprising administering to the subject a therapeutically effective amount of a polypeptide, or a therapeutically effective amount of a vector comprising a nucleic acid encoding the polypeptide,

wherein the amino acid sequence of the polypeptide consist of amino acids 16 to 25 of SEQ ID NO:

1, (X₁X₂APDVVAFV), wherein amino acid X₁ is a glutamine or a tryrosine and amino acid X₂ is a glutamic acid or a lecuine, and wherein the vector does not encode the amino acid sequence set forth as SEQ ID NO;

1,

thereby treating the PAGE4-expressing cancer in the subject.

2. The method of claim 1, wherein the amino acid sequence polypeptide consists of one of:

(a) amino acids 16 to 25 of SEQ ID NO;

1, wherein amino acid X₁ is a glutamine and amino acid X₂ is a leucine,

(b) amino acid 16 to 25 of SEQ ID NO;

1, wherein amino acid X₁ is a tyrosine and amino acid X₂ is a leucine.

3. The method of claim 2, wherein the amino acid sequence of the polypeptide consists of amino acids 16 to 25 of SEQ ID NO:

1, wherein amino acid X₁ is a glutamine and amino acid X₂ is a leucine.

4. The method of claim 2, wherein the amino acid sequence of the polypeptide consists of amino acids 16 to 25 of SEQ ID NO:

1, wherein amino acid X₁ is a tyrosine and amino acid X₂ is a leucine.

5. The method of claim 1, comprising administering to the subject a therapeutically effective amount of the vector encoding the polypeptide, wherein the vector is a plasmid, yeast, retrovirus, orthopox, avipox, fowlpox, capripox, suipox, adenoviral, herpes virus, alpha virus, baculovirus, Sindbis virus, vaccinia virus or poliovirus vector.

6. The method of claim 1, comprising administering to the subject a therapeutically effective amount of the vector encoding the polypeptide, wherein the vector is a first recombinant virus which has incorporated into a viral genome the polynucleotide encoding the isolated polypeptide, and wherein the method further comprises administering to the subject a therapeutically effective amount of a second recombinant virus which has incorporated into a viral genome thereof one or more genes or DNA sequences encoding a costimulatory molecule.

7. The method of claim 6, wherein the costimulatory molecule is one or more of B7-1, B7-2, LFA or ICAM-1.

8. The method of claim 6, wherein the first recombinant virus, the second recombinant virus, or the first and second recombinant viruses is selected from the group consisting of retrovirus vectors, orthopox vectors, avipox vectors, fowlpox vectors, capripox vectors, suipox vectors, adenoviral vectors, herpes virus vectors, alpha virus vectors, baculovirus vectors, Sindbis virus vectors, vaccinia virus vectors and poliovirus vectors.

9. The method of claim 6, wherein the first recombinant virus, the second recombinant virus, or the first and second recombinant virus is vaccinia or fowl pox virus.

10. The method of claim 6, wherein the second recombinant virus further comprises one or more exogenous DNA sequences encoding one or more immunostimulatory molecules, wherein the immunostimulatory molecule is selected from the group consisting of IL-2, ICAM-1, LFA-3, CD72, GM-CSF, TNF-α

, IFN-γ

, IL-12, and IL-6.

11. The method of claim 1, further comprising administering to the subject a therapeutically effective amount of one or more exogenous immunostimulatory molecules, wherein the immunostimulatory molecules are selected from the group consisting of IL-2, IL-12, RANTES, GM-CSF, TNF-α

, IFN-γ

, IFN-α

, IL-15, and G-CSF, or administering to the subject a combination more than one of the exogenous immunostimulatory molecules.

12. The method of claim 1, further comprising administering to the subject a therapeutically effective amount of a nucleic acid encoding one or more of IL-2, RANTES, GM-CSF, TNF-α

, IFN-γ

, IFN-α

, IL-15, G-CSF, LFA-3, CD72, B7-1, B7-2, OX-40L, 41 BBL and ICAM-1.

13. A polypeptide consisting of

amino acids 59 to 68 of SEQ ID NO:

1(X₃X₄GDCQEMDX₅), wherein amino acid X₃ is a valine, amino acid X₄ is a glutamic acid, and amino acid X₅ is a valine.

14. An isolated polynucleotide comprising a nucleic acid sequence encoding the polypeptide of claim 13.

15. A vector comprising the polynucleotide of claim 14.

18. A composition comprising a first recombinant virus which has incorporated into a viral genome a nucleic acid encoding the isolated polypeptide of claim 13 and a second recombinant virus which has incorporated into a viral genome thereof one or more genes or DNA sequences encoding a costimulatory molecule, wherein the composition is able to coinfect a host cell resulting in coexpression of the polypeptide and the encoding genes or DNA sequences encoding the costimulatory molecule.

19. The composition of claim 18, wherein the costimulatory molecule is one or more of B7-1, B7-2, LFA or ICAM-1.

20. The composition of claim 18, wherein the first recombinant virus, the second recombinant virus, or both the first and second recombinant viruses are selected from the group consisting of retrovirus vectors, orthopox vectors, avipox vectors, fowlpox vectors, capripox vectors, suipox vectors, adenoviral vectors, herpes virus vectors, alpha virus vectors, baculovirus vectors, Sindbis virus vectors, vaccinia virus vectors and poliovirus vectors.

21. The composition of claim 18, wherein the second recombinant virus further comprises one or more exogenous DNA sequences encoding one or more immunostimulatory molecules, wherein the immunostimulatory molecule is selected from the group consisting of IL-2, IL-12, ICAM-1, LFA-3, CD72, GM-CSF, INF-α

, IFN-γ

, and IL-6.

22. The composition of claim 21, wherein the composition further comprises an immunomodulating effective amount of at least one exogenous immunostimulatory molecule selected from the group consisting of IL-2, GM-CSF, TNF-α

, IL-12, and IL-6, or wherein the composition further comprises an immunomodulating effective amount of a combination of the exogenous immunolstimulatory molecules.

23. The composition of claim 18, wherein the first recombinant virus, the second recombinant virus, or the first and second recombinant virus is vaccinia or fowlpox virus.

27. A method for eliciting an immune response in a subject, comprising:

administering to a subject a therapeutically effective amount of the polypeptide of claim 13, or a polynucleotide encoding the polypeptide,

thereby producing an immune response to a polypeptide comprising the amino acid sequence set forth as SEQ ID NO;

1 in the subject.

28. The method of claim 27, further comprising administering an adjuvant to the subject.

29. The method of claim 27, further comprising administering to the subject a therapeutically effective amount of IL-2, IL-12, RANTES, GM-CSF, TNF-α

, IFN-γ

, G-CSF or a combination thereof.

30. The method of claim 27, further comprising administering to the subject a nucleic acid encoding one or more of IL-2, IL-12, RANTES, GM-CSF, TNF-α

, IFN-γ

, IFN-α

, IL-15, G-CSF, LFA-3, CD72, B7-1, B7-2, OX-40L, 41 BBL and ICAM-1.

36. A method for inhibiting the growth of a cancer cell in vitro, the method comprising:

(i) culturing cytotoxic T lymphocytes (CTLs) or CTL precursor cells with the polypeptide of claim 13 and an antigen presenting cell to produce activated CTLs that recognize the cancer cells, and

(ii) contacting the cancer cell with the activated CTLs,

thereby inhibiting the growth of the cancer cell in vitro, wherein the cancer cell is a reproductive cancer cell.

16. A plasmid or viral vector encoding a polypeptide

consisting of amino acids 59 to 68 SEQ ID NO:

1(X₃X₄GDCQEMDX₅), wherein amino acid X₃ is a valine, amino acid X₄ is a glutamic acid, and amino acid X₅ is a valine, and wherein the plasmid or viral vector does not encode SEQ ID NO;

1.

17. The vector of claim 16, wherein the vector is a retrovirus, orthopox, avipox, fowlpox, capripox, suipox, adenoviral, herpes virus, alpha virus, baculovirus, Sindbis virus, vaccinia virus or a poliovirus viral vector.

24. A pharmaceutical composition comprising the plasmid Or viral vector of claim 16, and a pharmaceutically acceptable carrier.

25. An isolated host cell transformed with the plasmid or viral vector of claim 16.

26. The isolated host cell of claim 25, wherein the host cell is a dendritic cell or a tumor cell.

31. A method of enhancing an immune response against cells expressing PAGE4 in a mammal comprising:

infecting cells in vitro with a therapeutically effective amount of the vector of claim 16, wherein the vector is a viral vector, to produce infected cells expressing the immunogenic PAGE4 polypeptide and

administering an amount of infected cells to a mammal afflicted with cells expressing a PAGE4 protein, thereby enhancing the immune response.

32. The method of claim 31, wherein the cells in vitro are dendritic cells or tumor cells.

33. The method of claim 31, further comprising administering an adjuvant to the subject.

34. The method of claim 31, further comprising administering to the subject a therapeutically effective amount of IL-2, IL-12, RANTES, GM-CSF, TNF-α

, IFN-γ

, IFN-α

, IL-15, G-CSF or a combination thereof.

35. The method of claim 31, further comprising administering to the subject an nucleic acid encoding one or more of IL-2, IL-12, RANTES, GM-CSF, TNF-α

, IFN-γ

, IFN-α

, IL-15, G-CSF, LFA-3, CD72, B7-1, B7-2, OX-40L, 41 BBL and ICAM-1.