Immunogenic tumor antigens: nucleic acids and polypeptides encoding the same and methods of use thereof

• US 20030017159A1
• Filed: 05/01/2002
• Published: 01/23/2003
• Est. Priority Date: 05/02/2001
• Status: Abandoned Application

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: Yang, Xiao-Feng, Ritz, Jerome, Wu, Catherine J.
• Application Number:
  US10/136,417
• Publication Number:
  US 20030017159A1
• Time in Patent Office: Days
• US Class Current: 424/155.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 2239/48 Blood cells, e.g. leukemia or lymphoma
• 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 39/461 characterised by the cell type used
• CPC Class Codes: A61K 39/4644 Cancer antigens
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 14/4748 Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
• CPC Class Codes: C07K 16/3061 Blood cells

Abstract

The invention provides human chronic myelocytic leukemia-like proteins (CML protein) and isolated nucleic acid molecules encoding the same. Also provided are antibodies that immunospecifically-bind to CML polypeptides or polynucleotides, or derivatives, variants, mutants, or fragments thereof. The invention additionally provides methods in which CML polypeptides, polynucleotides, and antibodies are used in the detection, prevention, and treatment of a broad range of pathological states, and methods of treating malignancy-related disorders by modulating activity or expression of CML proteins.

Claims

1. A method of treating or delaying the onset of an malignancy-associated disorder, said method comprising administering to a subject in need thereof an antibody to the polypeptide selected from the group consisting of SEQ ID NO:

2 and SEQ ID NO;

4 in an amount sufficient to treat or prevent said malignancy-associated disorder in said subject.

2. The method of claim 1 wherein the subject is a human.

3. The method of claim 1 wherein the malignancy-associated disorder is selected from the group consisting of leukemia and solid tumors.

4. The method of claim 1 wherein the malignancy-associated disorder comprises chronic myelocytic leukemia.

5. A method for determining the presence of or predisposition to a disease associated with altered levels of SEQ ID NO:

2 or SEQ ID NO;

4 in a first mammalian subject, said method comprising;

(a) providing a protein sample from said first mammalian subject;

(b) providing a control protein sample from a second mammalian subject known not to have or be predisposed to said disease;

(c) measuring the amount of SEQ ID NO;

2 or SEQ ID NO;

4 polypeptide in said subject sample; and

(d) comparing the amount of SEQ ID NO;

2 or SEQ ID NO;

4 polypeptide in said subject protein sample to the amount of SEQ ID NO;

2 or SEQ ID NO;

4 polypeptide in said control protein sample,

wherein an alteration in the expression level of the SEQ ID NO;

2 or SEQ ID NO;

4 polypeptide in the first subject sample as compared to the control sample indicates the presence or predisposition to said disease.

6. A method for determining the presence of or predisposition to a disease associated with altered levels of the nucleic acid of SEQ ID NO:

1 or SEQ ID NO;

3 in a first mammalian subject, said method comprising;

(a) providing a nucleic acid sample from said first mammalian subject;

(b) providing a control nucleic acid sample from a second mammalian subject known not to have or be predisposed to said disease;

(c) measuring the amount of SEQ ID NO;

1 or SEQ ID NO;

3 in said subject sample; and

(d) comparing the amount of SEQ ID NO;

1 or SEQ ID NO;

3 in said subject nucleic acid sample to the amount of SEQ ID NO;

1 or SEQ ID NO;

3 in said control nucleic acid sample,

wherein an alteration in the expression level of SEQ ID NO;

1 or SEQ ID NO;

3 in the first subject sample as compared to the control sample indicates the presence or predisposition to said disease.

7. A method of treating a pathological state in a mammal, the method comprising administering to the mammal a SEQ ID NO:

2 or SEQ ID NO;

4 polypeptide in an amount sufficient to alleviate the pathological state, wherein the polypeptide has an amino acid sequence at least 95% identical to the SEQ ID NO;

2 or SEQ ID NO;

4 polypeptide, or a biologically active fragment thereof

8. A method of treating a pathological state in a mammal, the method comprising administering to the mammal an antibody to a SEQ ID NO:

2 or SEQ ID NO;

4 polypeptide in an amount sufficient to alleviate the pathological state.

9. The method of claim 8 wherein the pathological state is selected from the group consisting of leukemia and a solid tumor.

10. The method of claim 8 wherein the pathological state comprises chronic myelocytic leukemia.

11. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of:

(a) a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS;

2 and 4;

(b) a variant of a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS;

2 and 4, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of the amino acid residues from the amino acid sequence of said mature form;

(c) an amino acid sequence selected from the group consisting SEQ ID NOS;

2 and 4; and

(d) a variant of an amino acid sequence selected from the group consisting of SEQ ID NOS;

2 and 4, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of amino acid residues from said amino acid sequence.

12. The polypeptide of claim 11, wherein said polypeptide comprises the amino acid sequence of a naturally-occurring allelic variant of an amino acid sequence selected from the group consisting SEQ ID NOS:

2 and 4.

13. The polypeptide of claim 11, wherein said allelic variant comprises an amino acid sequence that is the translation of a nucleic acid sequence differing by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NOS:

1 and 3.

14. The polypeptide of claim 11, wherein the amino acid sequence of said variant comprises a conservative amino acid substitution.

16. The nucleic acid molecule of claim 15, wherein the nucleic acid molecule comprises the nucleotide sequence of a naturally-occurring allelic nucleic acid variant.

17. The nucleic acid molecule of claim 15, wherein the nucleic acid molecule encodes a polypeptide comprising the amino acid sequence of a naturally-occurring polypeptide variant.

18. The nucleic acid molecule of claim 15, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NOS:

1 and 3.

19. The nucleic acid molecule of claim 15, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of:

(a) a nucleotide sequence selected from the group consisting of SEQ ID NOS;

1 and 3;

(b) a nucleotide sequence differing by one or more nucleotides from a nucleotide sequence selected from the group consisting of SEQ ID NOS;

1 and 3, provided that no more than 20% of the nucleotides differ from said nucleotide sequence;

(c) a nucleic acid fragment of (a); and

(d) a nucleic acid fragment of (b).

20. The nucleic acid molecule of claim 15, wherein said nucleic acid molecule hybridizes under stringent conditions to a nucleotide sequence chosen from the group consisting SEQ ID NOS:

1 and 3, or a complement of said nucleotide sequence.

21. The nucleic acid molecule of claim 15, wherein the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of:

(a) a first nucleotide sequence comprising a coding sequence differing by one or more nucleotide sequences from a coding sequence encoding said amino acid sequence, provided that no more than 20% of the nucleotides in the coding sequence in said first nucleotide sequence differ from said coding sequence;

(b) an isolated second polynucleotide that is a complement of the first polynucleotide; and

p1 (c) a nucleic acid fragment of (a) or (b).

22. A vector comprising the nucleic acid molecule of claim 15.

23. The vector of claim 22, further comprising a promoter operably-linked to said nucleic acid molecule.

24. A cell comprising the vector of claim 23.

25. An antibody that binds immunospecifically to the polypeptide of claim 11.

26. The antibody of claim 25, wherein said antibody is a monoclonal antibody.

27. The antibody of claim 25, wherein the antibody is a humanized antibody.

28. A method for determining the presence or amount of the polypeptide of claim 11 in a sample, the method comprising:

(a) providing the sample;

(b) contacting the sample with an antibody that binds immunospecifically to the polypeptide; and

(c) determining the presence or amount of antibody bound to said polypeptide,

thereby determining the presence or amount of polypeptide in said sample.

29. A method for determining the presence or amount of the nucleic acid molecule of claim 15 in a sample, the method comprising:

(a) providing the sample;

(b) contacting the sample with a probe that binds to said nucleic acid molecule; and

(c) determining the presence or amount of the probe bound to said nucleic acid molecule,

thereby determining the presence or amount of the nucleic acid molecule in said sample.

30. The method of claim 29 wherein presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type.

31. The method of claim 30 wherein the cell or tissue type is cancerous.

32. The method of claim 31 wherein the cancer is selected from leukemia and a solid tumor.

33. The method of claim 32 wherein the leukemia is chronic myelocytic leukemia.

34. A method of identifying an agent that binds to a polypeptide of claim 11, the method comprising:

(a) contacting said polypeptide with said agent; and

(b) determining whether said agent binds to said polypeptide.

35. The method of claim 34 wherein the agent is a cellular receptor or a downstream effector.

36. A method for identifying an agent that modulates the expression or activity of the polypeptide of claim 11, the method comprising:

(a) providing a cell expressing said polypeptide;

(b) contacting the cell with said agent, and

(c) determining whether the agent modulates expression or activity of said polypeptide,

whereby an alteration in expression or activity of said peptide indicates said agent modulates expression or activity of said polypeptide.

37. A method for modulating the activity of the polypeptide of claim 11, the method comprising contacting a cell sample expressing the polypeptide of said claim with a compound that binds to said polypeptide in an amount sufficient to modulate the activity of the polypeptide.

38. A pharmaceutical composition comprising the polypeptide of claim 11 and a pharmaceutically-acceptable carrier.

39. A pharmaceutical composition comprising the nucleic acid molecule of claim 15 and a pharmaceutically-acceptable carrier.

40. A pharmaceutical composition comprising the antibody of claim 25 and a pharmaceutically-acceptable carrier.

41. A kit comprising in one or more containers, the pharmaceutical composition of claim 38.

42. A kit comprising in one or more containers, the pharmaceutical composition of claim 39.

43. A kit comprising in one or more containers, the pharmaceutical composition of claim 40.

15. An isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of:

(a) a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS;

2 and 4;

(b) a variant of a mature form of an amino acid sequence selected from the group consisting of SEQ ID NOS;

2 and 4, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of the amino acid residues from the amino acid sequence of said mature form;

(c) an amino acid sequence selected from the group consisting of SEQ ID NOS;

2 and 4;

(d) a variant of an amino acid sequence selected from the group consisting SEQ ID NOS;

2 and 4, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of amino acid residues from said amino acid sequence;

(e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising an amino acid sequence chosen from the group consisting of SEQ ID NOS;

2 and 4, or a variant of said polypeptide, wherein one or more amino acid residues in said variant differs from the amino acid sequence of said mature form, provided that said variant differs in no more than 15% of amino acid residues from said amino acid sequence; and

(f) a nucleic acid molecule comprising the complement of (a), (b), (c), (d) or (e).