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1. (WO2011162904) MULTIDOMAIN BIOTAGS FOR CANCER DETECTION, DIAGNOSIS AND THERAPY AND METHODS OF THEIR USE PRIORITY STATEMENT
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

CLAIMS

What is claimed is:

1 . A single chain variable fragments (scFv) or single domain variable fragments (sdFv) comprising an amino acid sequence selected from SEQ ID NO:280-297.

2. A biotag for targeting a cancer biomarker comprising:

a cancer biomarker binding domain,

an internalization domain;

an endosomal escape domain;

a lysosomal escape domain;

a reporter binding domain; and

a reporter, wherein the reporter is a diagnostic agent.

3. The biotag of claim 2, wherein the cancer biomarker is ERBB 1 -4, EGFRvlll or Transferrin Receptor (TfR).

4. The biotag of claim 2, wherein the binding domain is an scFv, an sdFv, a complementarity determining region (CDR) or a specificity determination residue (SDR) modified CDR.

5. The biotag of claim 2, wherein the binding domain comprises an amino acid sequence selected from SEQ ID NO:280-297.

6. The biotag of claim 2, wherein the reporter binding domain is a metal binding domain.

7. The biotag of claim 6, wherein the reporter is a metal nanoparticle tag chelated to the metal binding domain.

8. The biotag of claim 7, wherein the metal nanoparticle tag is a noble metal.

9. The biotag of claim 8, wherein the noble metal a gold nanoparticle comprising one or more gold crystals.

10. The biotag of claim 8, where in the noble metal is Pt, Pd, Ag.

1 1 . The biotag of claim 7, wherein the metal nanoparticle tag is a superparamagnetic metal.

12. The biotag of claim 1 1 , wherein superparamagnetic metal is Gd, Eu, Fe, Ni, or Co.

13. The biotag of claim 7, wherein the metal nanoparticle tag is a core-shell nanoparticle, the core shell nanoparticle comprising an inner superparamagnetic metal core and an outer noble metal shell.

14. The biotag of claim 2, wherein the diagnostic agent is a fluorescent agent.

15. A targeted contrast composition for use with a diagnostic imaging technique comprising:

a contrast agent; and

a biotag for targeting a cancer biomarker.

16. The targeted contrast composition of claim 15, wherein the biotag comprises:

a cancer biomarker binding domain,

an internalization domain;

an endosomal escape domain;

a lysosomal escape domain;

a reporter binding domain; and

a reporter, wherein the reporter is a diagnostic agent.

17. The targeted contrast composition of claim 16, wherein the cancer biomarker is ERBB 1 -4, EGFRvlll or Transferrin Receptor (TfR).

18. The targeted contrast composition of claim 16, wherein the binding domain is an scFv, an sdFv, a complementarity determining region (CDR) or a specificity

determination residue (SDR) modified CDR.

19. The targeted contrast of claim 18, wherein the binding domain comprises an amino acid sequence selected from SEQ ID NO:280-297.

20. The targeted contrast composition of claim 15, wherein the diagnostic imaging technique is a radiography, CT, MRI, NMR or Raman.

21 . A method for detecting and/or diagnosing a cancer in a subject, the method comprising:

administering an effective dose of a biotag, a contrast agent or both to the subject, the biotag that targets a cancer biomarker;

exposing the subject to a diagnostic imaging technique;

detecting a population of cells expressing the cancer biomarker; and

quantifying the expression of the cancer biomarker in the population of cells; wherein an increased expression of the cancer biomarker indicates that the subject has cancer.

22. The method of claim 21 , wherein the biotag comprises

a cancer biomarker binding domain,

an internalization domain;

an endosomal escape domain;

a lysosomal escape domain;

a reporter binding domain; and

a reporter, wherein the reporter is a diagnostic agent.

23. The method of claim 22, wherein the cancer biomarker is ERBB 1 -4, EGFRvlll or Transferrin Receptor (TfR)..

24. The method of claim 22, wherein the binding domain comprises an amino acid sequence selected from SEQ ID NO:280-297.

25. The method of claim 22, wherein the reporter binding domain is a metal binding domain.

26. The method of claim 25, wherein the reporter is a metal nanoparticle tag chelated to the metal binding domain.

27. The method of claim 26, wherein the metal nanoparticle tag is a noble metal.

28. The method of claim 27, wherein the noble metal a gold nanoparticle comprising one or more gold crystals.

29. The method of claim 27, where in the noble metal is Pt, Pd, Ag.

30. The method of claim 26, wherein the metal nanoparticle tag is a

superparamagnetic metal.

31 . The method of claim 30, wherein superparamagnetic metal is Gd, Eu, Fe, Ni, or Co.

32. The method of claim 26, wherein the metal nanoparticle tag is a core-shell nanoparticle, the core shell nanoparticle comprising an inner superparamagnetic metal core and an outer noble metal shell.

33. The method of claim 22, wherein the diagnostic agent is a fluorescent agent.

34. The method of claim 21 , wherein the diagnostic imaging technique is an X-Ray, computed tomography (CT), magnetic resonance imaging (MRI), nuclear magnetic resonance (NMR), Raman.

35. The method of claim 34, wherein the diagnostic imaging technique allows for localization of a malignant tumor.

36. A method for diagnosing the aggressiveness of a cancer in a subject, the method comprising:

administering an effective dose of a biotag, a contrast agent or both to the subject, the biotag that targets a cancer biomarker;

exposing the subject to a diagnostic imaging technique;

detecting a population of cells expressing the cancer biomarker; and

quantifying the expression of the cancer biomarker in the population of cells;

wherein an increased expression of biomarker indicates that the cancer is a more aggressive cancer.

37. The method of claim 36, wherein the biotag comprises:

a cancer biomarker binding domain,

an internalization domain;

an endosomal escape domain;

a lysosomal escape domain;

a reporter binding domain; and

a reporter, wherein the reporter is a diagnostic agent.

38. The method of claim 37, wherein the cancer biomarker is ERBB 1 -4, EGFRvlll or Transferrin Receptor (TfR)..

39. The method of claim 37, wherein the binding domain comprises an amino acid sequence selected from SEQ ID NO:280-297.

40. The method of claim 37, wherein the reporter binding domain is a metal binding domain.

41 . The method of claim 37, wherein the reporter is a metal nanoparticle tag chelated to the metal binding domain.

42. The method of claim 41 , wherein the metal nanoparticle tag is a noble metal.

43. The method of claim 42, wherein the noble metal a gold nanoparticle comprising one or more gold crystals.

44. The method of claim 42, where in the noble metal is Pt, Pd, Ag.

45. The method of claim 41 , wherein the metal nanoparticle tag is a

superparamagnetic metal.

46. The method of claim 45, wherein superparamagnetic metal is Gd, Eu, Fe, Ni, or Co.

47. The method of claim 41 , wherein the metal nanoparticle tag is a core-shell nanoparticle, the core shell nanoparticle comprising an inner superparamagnetic metal core and an outer noble metal shell.

48. The method of claim 37, wherein the diagnostic agent is a fluorescent agent.

49. The method of claim 36, wherein the diagnostic imaging technique is a radiography, CT, MRI, NMR, or Raman.

50. A method for detecting and/or diagnosing cancer in a subject, the method comprising:

incubating a physiological fluid sample that contains circulating tumor cells or is suspected of containing circulating tumor cells with a biotag that targets a cancer biomarker expressed on circulating tumor cells; and

isolating cells bound to the biotag from cells not bound to the biotag, wherein having cells bound to the biotag is indicative of cancer.

51 . The method of claim 50, wherein the biotag comprises:

a cancer biomarker binding domain,

an internalization domain;

an endosomal escape domain;

a lysosomal escape domain;

a reporter binding domain; and

a reporter, wherein the reporter is a diagnostic agent.

52. The method of claim 50, wherein the cancer biomarker is ERBB 1 -4, EGFRvlll or Transferrin Receptor (TfR).

53. The method of claim 51 , wherein the binding domain comprises an amino acid sequence selected from SEQ ID NO:280-297.

54. The method of claim 51 , wherein the reporter binding domain is a metal binding domain.

55. The method of claim 54, wherein the reporter is a metal nanoparticle tag chelated to the metal binding domain.

56. The method of claim 55, wherein the metal nanoparticle tag is a noble metal.

57. The method of claim 56, wherein the noble metal a gold nanoparticle comprising one or more gold crystals.

58. The method of claim 56, where in the noble metal is Pt, Pd, Ag.

59. The method of claim 55, wherein the metal nanoparticle tag is a

superparamagnetic metal.

60. The method of claim 59, wherein superparamagnetic metal is Gd, Eu, Fe, Ni, or Co.

61 . The method of claim 54, wherein the metal nanoparticle tag is a core-shell nanoparticle, the core shell nanoparticle comprising an inner superparamagnetic metal core and an outer noble metal shell.

62. The method of claim 51 , wherein the diagnostic agent is a fluorescent agent.

63. The method of claim 50, wherein isolation of the cells bound to the biotag is accomplished by a magnet, a cell cytometry method or by establishing a mass gradient.

64. The method of claim 50, wherein the physiological fluid is blood, serum, plasma, urine, prostate fluid, tears, mucus ascites fluid, oral fluid, saliva, semen, seminal fluid, mucus, stool, sputum, cerebrospinal fluid (CSF), bone marrow, lymph, or fetal fluid.

64. A method for detecting circulating tumor cells in a physiological fluid sample comprising the steps of:

a) exposing the physiological fluid sample from a subject having or suspected of having cancer to a biotag that targets a cancer biomarker; and

b) isolating cells from the sample that bind to the biotag;

c) determining that circulating tumor cells are present in the sample when cells are bound to the biotag.

65. The method of claim 64, wherein the biotag comprises:

a cancer biomarker binding domain,

an internalization domain;

an endosomal escape domain;

a lysosomal escape domain;

a reporter binding domain; and

a reporter, wherein the reporter is a diagnostic agent.

66. The method of claim 64, wherein the cancer biomarker is ERBB 1 -4, EGFRvlll or Transferrin Receptor (TfR).

67. The method of claim 65, wherein the binding domain comprises an amino acid sequence selected from SEQ ID NO:280-297.

68. The method of claim 65, wherein the reporter binding domain is a metal binding domain.

69. The method of claim 68, wherein the reporter is a metal nanoparticle tag chelated to the metal binding domain.

70. The method of claim 69, wherein the metal nanoparticle tag is a noble metal.

71 . The method of claim 70, wherein the noble metal a gold nanoparticle comprising one or more gold crystals.

72. The method of claim 70, where in the noble metal is Pt, Pd, Ag.

73. The method of claim 59, wherein the metal nanoparticle tag is a

superparamagnetic metal.

74. The method of claim 73, wherein superparamagnetic metal is Gd, Eu, Fe, Ni, or Co.

75. The method of claim 51 , wherein the metal nanoparticle tag is a core-shell nanoparticle, the core shell nanoparticle comprising an inner superparamagnetic metal core and an outer noble metal shell.

76. The method of claim 65, wherein the diagnostic agent is a fluorescent agent.

77. The method of claim 64, wherein isolation of the cells bound to the biotag is accomplished by a magnet, a cell cytometry method or by establishing a mass gradient.

78. The method of claim 64, wherein the physiological fluid is blood, serum, plasma, urine, prostate fluid, tears, mucus ascites fluid, oral fluid, saliva, semen, seminal fluid, mucus, stool, sputum, cerebrospinal fluid (CSF), bone marrow, lymph, or fetal fluid.

79. The method of claim 64, wherein the presence of cells that bind the biotag is indicative of metastasizing cells or metastasis of a tumor.