Methods for identifying tumors responsive to treatment with HER dimerization inhibitors (HDIs)

• US 20060204505A1
• Filed: 03/07/2006
• Published: 09/14/2006
• Est. Priority Date: 03/08/2005
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Sliwkowski, Mark X., Eberhard, David A.
• Application Number:
  US11/370,304
• Publication Number:
  US 20060204505A1
• Time in Patent Office: Days
• US Class Current: 424/155.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C12Q 1/485 involving kinase
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity
• CPC Class Codes: G01N 33/574 for cancer
• CPC Class Codes: G01N 33/57407 Specifically defined cancers
• CPC Class Codes: G01N 33/57415 of breast
• CPC Class Codes: G01N 33/57449 of ovaries

Abstract

Tumors are identified as responsive to treatment with HER dimerization inhibitors (HDIs) are identified by treating a HER expressing tumor with an HDI (which may be the same or different from that contemplated for treatment), and determining the reactivity of the tumor with the HDI. Lack of or diminished reactivity is an indication that the tumor is likely to be responsive to treatment with the dimerization ihibitor.

Claims

1. A method for predicting the responsiveness of a HER expressing tumor to treatment with a first HER dimerization inhibitor (HDI) comprising determining the reactivity of said tumor with a second HDI, wherein no or low reactivity predicts responsiveness to treatment with said first HDI.

2. The method of claim 1 wherein said tumor expresses HER2.

3. The method of claim 2 wherein said tumor does not over-express HER2.

4. The method of claim 2 wherein said tumor is characterized by low levels of HER2 expression.

5. The method of claim 1 wherein said first and second HDIs are the same.

6. The method of claim 1 wherein said first and second HDIs are different.

7. The method of claim 1 wherein at least one of said first and second HDIs is an antibody.

8. The method of claim 7 wherein at least one of said first and second HDIs is an anti-HER antibody.

9. The method of claim 8 wherein said antibody binds to a HER receptor selected from the group consisting of EGFR, HER2, and HER3.

10. The method of claim 9 wherein said antibody is an anti-HER2 antibody.

11. The method of claim 10 wherein said antibody binds to domain II of HER2 extracellular domain.

12. The method of claim 10 wherein said antibody binds to a junction between domains I, II and III of HER2 extracellular domain.

13. The method of claim 10 wherein each of said first HDI and said second HDI is an anti-HER2 antibody.

14. The method of claim 13 wherein the first and second anti-HER2 antibodies bind to essentially the same region of HER2.

15. The method of claim 10 wherein said first HDI is a humanized or human 2C4 antibody.

16. The method of claim 15 wherein said first HDI comprises the variable light and variable heavy amino acid sequences in SEQ ID Nos. 5 and 6, respectively.

17. The method of claim 16 wherein said first HDI is rhuMAb 2C4 (pertuzumab).

18. The method of claim 17 wherein said second HDI is a murine 2C4 antibody.

19. The method of claim 9 wherein at least one of said anti-HER antibodies is a naked antibody.

20. The method of claim 9 wherein at least one of said anti-HER antibodies is an intact antibody.

21. The method of claim 9 wherein at least one of said anti-HER antibodies is an antibody fragment comprising a HER binding region.

22. The method of claim 1 wherein said tumor is cancer.

23. The method of claim 22 wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, non-small cell lung cancer (NSCLC), prostate cancer, and colorectal cancer.

24. The method of claim 23 wherein said cancer is metastatic breast cancer (MBC).

25. The method of claim 23 wherein the cancer is ovarian, peritoneal, or fallopian tube cancer.

26. The method of claim 25 wherein the cancer is advanced, refractory or recurrent ovarian cancer.

27. The method of claim 1 further comprising the step of administering an effective amount of said first HDI to a subject whose tumor has been predicted to be responsive to treatment with said first HDI.

69. The method of claim 1 or claim 36, wherein reactivity is determined by (a) contacting a biological sample comprising tumor cells from said tumor with said second HDI in vitro, under conditions conducive to the formation of a HER2 heterodimer, and (b) monitoring the binding of said second HDI to said tumor cells.

70. The method of claim 69 wherein said biological sample naturally provides conditions conducive to heterodimer formation.

71. The method of claim 69 wherein said contacting is performed after incubating said tumor cells with a HER ligand inducing HER dimerization.

72. The method of claim 71 wherein said HER ligand is selected from the group consisting of epidermal growth factor (EGF), transforming growth factor alpha (TGF-a), amphiregulin, heparin binding epidermal growth factor (HB-EGF), betacellulin, epiregulin, alpha, beta and gamma heregulins;

neu differentiation factors (NDFs), glial growth factors (GGFs);

acetylcholine receptor inducing activity (ARIA);

sensory and motor neuron derived factor (SMDF), neuregulin-2 (NRG-2), neuregulin-3, neuregulin-4, betacellulin and epiregulin.

73. The method of claim 72 wherein said HER ligand is a heregulin.

74. The method of claim 69 wherein said tumor cells are immobilized on a solid support.

75. The method of claim 74 wherein HDI binding is monitored by an immunoassay.

76. The method of claim 75 wherein said immunoassay is performed in an ELISA format.

77. The method of claim 71 wherein said binding is monitored at at least two ligand concentrations.

78. The method of claim 77 wherein said binding is monitored at at least two HDI concentrations.

28. The method of clam 27 wherein said subject is a human patient.

29. The method of claim 28 wherein said first HDI is administered as a single anti-tumor agent.

30. The method of claim 28 comprising administering a further therapeutic agent to said patient.

31. The method of claim 30 wherein said further therapeutic agent is selected from the group consisting of chemotherapeutic agent, HER antibody, antibody directed against a tumor associated antigen, anti-hormonal compound, cardioprotectant, cytokine, EGFR-targeted drug, anti-angiogenic agent, tyrosine kinase inhibitor, COX inhibitor, non-steroidal anti-inflammatory drug, farnesyl transferase inhibitor, antibody that binds oncofetal protein CA 125, HER2 vaccine, HER targeting therapy, Raf or ras inhibitor, liposomal doxorubicin, topptecan, taxane, dual tyrosine kinase inhibitor, TLK286, EMD-7200, a medicament that treats nausea, a medicament that prevents or treats skin rash or standard acne therapy, a medicament that treats or prevents diarrhea, a body temperature-reducing medicament, and a hematopoietic growth factor.

32. The method of claim 31 wherein the second therapeutic agent is a chemotherapeutic agent.

33. The method of claim 32 wherein the chemotherapeutic agent is an antimetabolite chemotherapeutic agent.

34. The method of claim 33 wherein the antimetabolite chemotherapeutic agent is gemcitabine.

35. The method of claim 31 wherein the second therapeutic agent is trastuzumab, erlotinib, or bevacizumab.

36. A method for selecting patients diagnosed with a HER expressing tumor for treatment with a first HER dimerization inhibitor (HDI), comprising determining the reactivity of tumor samples obtained from said patients with a second HDI, and selecting patients whose tumor samples show no or low reactivity with said second HDI, for treatment with said first HDI.

37. The method of claim 36 wherein said tumor expresses HER2.

38. The method of claim 37 wherein said tumor does not over-express HER2.

39. The method of claim 37 wherein said tumor is characterized by low levels of HER2 expression.

40. The method of claim 36 wherein said first and second HDIs are the same.

41. The method of claim 36 wherein said first and second HDIs are different.

42. The method of claim 36 wherein at least one of said first and second HDIs is an antibody.

43. The method of claim 42 wherein at least one of said first and second HDIs is an anti-HER antibody.

44. The method of claim 43 wherein said antibody binds to a HER receptor selected from the group consisting of EGFR, HER2, and HER3.

45. The method of claim 44 wherein said antibody is an anti-HER2 antibody.

46. The method of claim 45 wherein said antibody binds to domain II of HER2 extracellular domain.

47. The method of claim 45 wherein said antibody binds to a junction between domains I, II and III of HER2 extracellular domain.

48. The method of claim 45 wherein both said first HDI and said second HDI are anti-HER2 antibodies.

49. The method of claim 48 wherein said first HDI is a humanized or human 2C4 antibody.

50. The method of claim 48 wherein said first HDI comprises the variable light and variable heavy amino acid sequences in SEQ ID Nos. 5 and 6, respectively.

51. The method of claim 48 wherein said first HDI is rhuMAb 2C4 (pertuzumab).

52. The method of claim 48 wherein said second HDI is a murine 2C4 antibody.

53. The method of claim 43 wherein at least one of said anti-HER antibodies is a naked antibody.

54. The method of claim 43 wherein at least one of said anti-HER antibodies is an intact antibody.

55. The method of claim 43 wherein at least one of said anti-HER antibodies is an antibody fragment comprising a HER binding region.

56. The method of claim 36 wherein said tumor is cancer.

57. The method of claim 56 wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, non-small cell lung cancer (NSCLC), prostate cancer, and colorectal cancer.

58. The method of claim 57 wherein said cancer is metastatic breast cancer (MBC).

59. The method of claim 57 wherein the cancer is ovarian, peritoneal, or fallopian tube cancer.

60. The method of claim 59 wherein the cancer is advanced, refractory or recurrent ovarian cancer.

61. The method of claim 36 further comprising the step of administering to a patient selected an effective amount of said second HDI.

62. The methof of claim 61 wherein said second HDI is administered as a single anti-tumor agent.

63. The method of claim 61 comprising administering a further therapeutic agent to said patient.

64. The method of claim 63 wherein said further therapeutic agent is selected from the group consisting of chemotherapeutic agent, HER antibody, antibody directed against a tumor associated antigen, anti-hormonal compound, cardioprotectant, cytokine, EGFR-targeted drug, anti-angiogenic agent, tyrosine kinase inhibitor, COX inhibitor, non-steroidal anti-inflammatory drug, farnesyl transferase inhibitor, antibody that binds oncofetal protein CA 125, HER2 vaccine, HER targeting therapy, Raf or ras inhibitor, liposomal doxorubicin, topotecan, taxane, dual tyrosine kinase inhibitor, TLK286, EMD-7200, a medicament that treats nausea, a medicament that prevents or treats skin rash or standard acne therapy, a medicament that treats or prevents diarrhea, a body temperature-reducing medicament, and a hematopoietic growth factor.

65. The method of claim 64 wherein the further therapeutic agent is a chemotherapeutic agent.

66. The method of claim 64 wherein the chemotherapeutic agent is an antimetabolite chemotherapeutic agent.

67. The method of claim 66 wherein the antimetabolite chemotherapeutic agent is gemcitabine.

68. The method of claim 63 wherein the further therapeutic agent is trastuzumab, erlotinib, or bevacizumab.