ANTI-HER2 ANTIBODIES AND IMMUNOCONJUGATES

• US 20160096893A1
• Filed: 09/11/2015
• Published: 04/07/2016
• Est. Priority Date: 09/12/2014
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Dennis, Mark, Junutula, Jagath Reddy, Phillips, Gail Lewis, Pillow, Thomas Harden, Sliwkowski, Mark X., Chen, Xiaocheng
• Granted Patent: US 9,518,118 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 47/68 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61K 47/6863 the tumour determinant being from stomach or intestines cancer cell
• CPC Class Codes: A61K 49/00 Preparations for testing in vivo
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/3015 Breast
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• 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: C07K 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/82 : Translation products from oncogenes
• CPC Class Codes: G01N 33/57415 : of breast
• CPC Class Codes: G01N 33/57446 : of stomach or intestine
• CPC Class Codes: G01N 33/57492 : involving compounds localized on the membrane of tumor or cancer cells

Abstract

The invention provides anti-HER2 antibodies and immunoconjugates and methods of using the same.

Claims

1. An isolated antibody that binds to HER2, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:

15;

(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO;

16;

(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO;

17;

(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO;

13; and

(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO;

14.

2. The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO:

11 and a light chain variable region comprising the sequence of SEQ ID NO;

10.

3. The antibody of claim 1, which is a monoclonal antibody.

4. The antibody of claim 1, which is a humanized or chimeric antibody.

5. The antibody of claim 1, which is an antibody fragment that binds HER2.

6. The antibody of claim 1, wherein HER2 is human HER2 comprising amino acids 23 to 1255 of SEQ ID NO:

1.

7. The antibody of claim 1, wherein the antibody binds to extracellular domain I of HER2.

8. The antibody of claim 7, wherein extracellular domain I of HER2 has the sequence of SEQ ID NO:

35.

9. The antibody of claim 1, which is an IgG1, IgG2a or IgG2b antibody.

10. The antibody of claim 1, wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A118C and S400C.

11. The antibody of claim 1, wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C.

12. The antibody of claim 1, wherein the antibody comprises:

a) a heavy chain comprising the sequence of SEQ ID NO;

19 and a light chain comprising the sequence of SEQ ID NO;

18;

or

b) a heavy chain comprising the sequence of SEQ ID NO;

19 and a light chain comprising the sequence of SEQ ID NO;

23;

or

c) a heavy chain comprising the sequence of SEQ ID NO;

24 and a light chain comprising the sequence of SEQ ID NO;

18.

13. The antibody of claim 1, wherein the antibody comprises the heavy chain constant region of SEQ ID NO:

28.

14. The antibody of claim 1, wherein the antibody comprises the light chain constant region of SEQ ID NO:

25.

17. An isolated nucleic acid encoding the antibody of claim 1.

18. A host cell comprising the nucleic acid of claim 17.

19. A method of producing an antibody comprising culturing the host cell of claim 18 so that the antibody is produced.

20. An immunoconjugate comprising the antibody of claim 1 and a cytotoxic agent.

21. The immunoconjugate of claim 20 having the formula Ab-(L-D)p, wherein:

(a) Ab is an isolated antibody that binds to HER2, wherein the antibody comprises (1) HVR-H1 comprising the amino acid sequence of SEQ ID NO;

15;

(2) HVR-H2 comprising the amino acid sequence of SEQ ID NO;

16;

(3) HVR-H3 comprising the amino acid sequence of SEQ ID NO;

17;

(4) HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12;

(5) HVR-L2 comprising the amino acid sequence of SEQ ID NO;

13; and

(6) HVR-L3 comprising the amino acid sequence of SEQ ID NO;

14;

(b) L is a linker;

(c) D is a cytotoxic agent; and

(d) p ranges from 1-8.

22. The immunoconjugate of claim 20, wherein the cytotoxic agent is selected from an auristatin, a maytansinoid, a calicheamicin, a pyrrolobenzodiazepine, a nemorubicin derivative, and a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI).

23. The immunoconjugate of claim 21, wherein the cytotoxic agent is a pyrrolobenzodiazepine of Formula A:

24. The immunoconjugate of claim 23, wherein D has the structure:

25. The immunoconjugate of claim 20, wherein the cytotoxic agent is a nemorubicin derivative.

26. The immunoconjugate of claim 21, wherein the cytotoxic agent has a structure selected from:

27. The immunoconjugate of claim 20, wherein the cytotoxic agent comprises a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI).

28. The immunoconjugate of claim 21, wherein the cytotoxic agent has the formula:

29. The immunoconjugate of claim 28, wherein the cytotoxic agent has a structure selected from:

30. The immunoconjugate of claim 21, wherein the linker is cleavable by a protease.

31. The immunoconjugate of claim 21, wherein the linker is acid-labile.

32. The immunoconjugate of claim 31, wherein the linker comprises hydrazone.

33. The immunoconjugate of claim 21, wherein the linker comprises a disulfide.

34. The immunoconjugate of claim 21 having a structure selected from:

35. The immunoconjugate of claim 21 having a formula selected from:

36. The immunoconjugate of claim 21, having a structure selected from:

37. The immunoconjugate of claim 21, wherein the cytotoxic agent comprises the structure:

38. The immunoconjugate of claim 21, wherein p ranges from 1.3-2.

39. A pharmaceutical formulation comprising the immunoconjugate of claim 21 and a pharmaceutically acceptable carrier.

40. The pharmaceutical formulation of claim 39, further comprising an additional therapeutic agent.

41. The pharmaceutical formulation of claim 40, wherein the additional therapeutic agent is an antibody or immunoconjugate that binds HER2.

42. The pharmaceutical formulation of claim 41, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to domain II of HER2, and/or (ii) an antibody or immunoconjugate that binds to domain IV or HER2.

43. The pharmaceutical formulation of claim 41, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to epitope 2C4, and/or (ii) an antibody or immunoconjugate that binds to epitope 4D5.

44. The pharmaceutical formulation of claim 40, wherein the additional therapeutic agent is selected from trastuzumab, trastuzumab-MCC-DM1 (T-DM1), and pertuzumab.

45. The pharmaceutical formulation of claim 40, further comprising (1) trastuzumab or T-DM1, and (2) pertuzumab.

46. A method of treating an individual having a HER2-positive cancer, the method comprising administering to the individual an effective amount of the immunoconjugate of claim 20.

47. The method of claim 46, wherein the HER2-positive cancer is breast cancer or gastric cancer.

48. The method of claim 47, wherein the HER2-positive breast cancer is early-stage breast cancer.

49. The method of claim 47, wherein the HER2-positive breast cancer is metastatic breast cancer.

50. The method of claim 46, further comprising administering an additional therapeutic agent to the individual.

51. A method of treating an individual having a HER2-positive cancer, the method comprising administering to the individual an effective amount of the immunoconjugate of claim 20 and at least one additional therapeutic agent to the individual.

52. The method of claim 51, wherein the additional therapeutic agent is an antibody or immunoconjugate that binds HER2.

53. The method of claim 52, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to domain II of HER2, and/or (ii) an antibody or immunoconjugate that binds to domain IV or HER2.

54. The method of claim 52, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to epitope 2C₄, and/or (ii) an antibody or immunoconjugate that binds to epitope 4 D5.

55. The method of claim 51, wherein the additional therapeutic agent is selected from trastuzumab, trastuzumab-MCC-DM1 (T-DM1), and pertuzumab.

56. The method of claim 51, wherein the additional therapeutic agents are (1) trastuzumab or T-DM1, and (2) pertuzumab.

57. The method of claim 51, wherein the HER2-positive cancer is breast cancer or gastric cancer.

58. The method of claim 57, wherein the HER2-positive breast cancer is metastatic breast cancer.

59. The method of claim 57, wherein the HER2-positive breast cancer is early-stage breast cancer.

60. The method of claim 46, wherein the HER2-positive cancer is recurrent cancer.

61. The method of claim 60, wherein the recurrent cancer is locally recurrent cancer.

62. The method of claim 46, wherein the HER2-positive cancer is advanced cancer.

63. The method of claim 46, wherein the HER2-positive cancer is non-resectable.

64. A method of treating an individual having a HER2-positive cancer, comprising:

a) subjecting the individual to neoadjuvant treatment with the immunoconjugate of any one of claim 20,

b) removing the cancer by definitive surgery, and

c) subjecting the individual to adjuvant treatment with the immunoconjugate of claim 20.

65. The method of claim 64, wherein the HER2-positive cancer is breast cancer or gastric cancer.

66. The method of claim 65, wherein the HER2-positive cancer is breast cancer.

67. A method of inhibiting proliferation of a HER2-positive cell, the method comprising exposing the cell to the immunoconjugate of claim 20 under conditions permissive for binding of the immunoconjugate to HER2 on the surface of the cell, thereby inhibiting proliferation of the cell.

68. The method of claim 67, wherein the cell is a breast cancer cell of a gastric cancer cell.

69. The antibody of claim 1 conjugated to a label.

70. The antibody of claim 69, wherein the label is a positron emitter.

71. The antibody of claim 70, wherein the positron emitter is ⁸⁹Zr.

72. A method of detecting human HER2 in a biological sample comprising contacting the biological sample with the anti-HER2 antibody of claim 1 under conditions permissive for binding of the anti-HER2 antibody to a naturally occurring human HER2, and detecting whether a complex is formed between the anti-HER2 antibody and a naturally occurring human HER2 in the biological sample.

73. The method of claim 72, wherein the biological sample is a breast cancer or gastric cancer sample.

74. A method for detecting a HER2-positive cancer comprising (i) administering a labeled anti-HER2 antibody to a subject having or suspected of having a HER2-positive cancer, wherein the labeled anti-HER2 antibody comprises the anti-HER2 antibody of claim 1, and (ii) detecting the labeled anti-HER2 antibody in the subject, wherein detection of the labeled anti-HER2 antibody indicates a HER2-positive cancer in the subject.

75. The method of claim 74, wherein the labeled anti-HER2 antibody comprises an anti-HER2 antibody conjugated to a positron emitter.

76. The method of claim 75, wherein the positron emitter is ⁸⁹Zr.

15. An isolated antibody that binds to HER2, wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO:

19 and a light chain comprising the sequence of SEQ ID NO;

23.

16. An isolated antibody that binds to HER2, wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO:

24 and a light chain comprising the sequence of SEQ ID NO;

18.