ANTI-FCRH5 ANTIBODIES

• US 20150098900A1
• Filed: 06/24/2014
• Published: 04/09/2015
• Est. Priority Date: 06/24/2013
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Ebens, Allen J., Hazen, Meredith C., Hongo, Jo-Anne, Johnston, Jennifer W., Junttila, Teemu T., Li, Ji, Polson, Andrew G.
• Granted Patent: US 10,435,471 B2
• Time in Patent Office: Days
• US Class Current: 424/1.49
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6879 the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• CPC Class Codes: A61K 51/1045 against animal or human tumor cells or tumor cell determinants
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/283 against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL

Abstract

The invention provides anti-FcRH5 antibodies and immunoconjugates and methods of using the same.

Claims

1. An isolated anti-FcRH5 antibody that binds an isoform c-specific region of the extracellular domain of FcRH5c.

2. The antibody of claim 1, wherein the isoform c-specific region comprises Ig-like domain 9.

3. The antibody of claim 1, wherein the isoform c-specific region comprises amino acids 743-850 of SEQ ID NO:

1.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

38, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

62, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

86; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

2, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

14, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

26.

5. The antibody of claim 4, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

50, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

74, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

98.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

39, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

63, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

87; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

3, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

15, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

27.

7. The antibody of claim 6, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

51, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

75, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

99.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

40, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

64, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

88; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

4, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

16, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

28.

9. The antibody of claim 8, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

52, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

76, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

100.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

41, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

65, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

89; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

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

17, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

29.

11. The antibody of claim 10, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

53, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

77, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

101.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

42, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

66, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

90; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

6, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

18, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

30.

13. The antibody of claim 12, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

54, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

78, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

102.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

43, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

67, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

91; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

7, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

19, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

31.

15. The antibody of claim 14, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

55, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

79, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

103.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

44, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

68, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

92; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

8, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

20, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

32.

17. The antibody of claim 16, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

56, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

80, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

104.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

45, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

69, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

93; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

9, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

21, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

33.

19. The antibody of claim 18, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

57, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

81, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

105.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

46, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

70, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

94; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

10, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

22, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

34.

21. The antibody of claim 20, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

58, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

82, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

106.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

47, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

71, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

95; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

11, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

23, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

35.

23. The antibody of claim 22, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

59, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

83, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

107.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

48, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

72, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

96; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

12, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

24, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

36.

25. The antibody of claim 24, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

60, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

84, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

108.

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

a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO;

49, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

73, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

97; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

13, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

25, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

37.

27. The antibody of claim 26, wherein the heavy chain comprises a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

61, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

85, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

109.

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

a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

111 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

110;

b) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

113 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

112;

c) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

115 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

114;

d) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

117 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

116;

e) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

119 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

118;

f) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

121 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

120;

g) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

123 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

122;

h) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

125 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

124;

i) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

127 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

126;

j) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

129 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

128;

k) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

131 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

130;

l) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

133 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

132;

or

m) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

135 and/or a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO;

134.

29. The antibody of claim 28, wherein the antibody comprises:

a) a VH sequence of SEQ ID NO;

111 and/or a VL sequence of SEQ ID NO;

110;

b) a VH sequence of SEQ ID NO;

113 and/or a VL sequence of SEQ ID NO;

112;

c) a VH sequence of SEQ ID NO;

115 and/or a VL sequence of SEQ ID NO;

114;

d) a VH sequence of SEQ ID NO;

117 and/or a VL sequence of SEQ ID NO;

116;

e) a VH sequence of SEQ ID NO;

119 and/or a VL sequence of SEQ ID NO;

118;

f) a VH sequence of SEQ ID NO;

121 and/or a VL sequence of SEQ ID NO;

120;

g) a VH sequence of SEQ ID NO;

123 and/or a VL sequence of SEQ ID NO;

122;

h) a VH sequence of SEQ ID NO;

125 and/or a VL sequence of SEQ ID NO;

124;

i) a VH sequence of SEQ ID NO;

127 and/or a VL sequence of SEQ ID NO;

126;

j) a VH sequence of SEQ ID NO;

129 and/or a VL sequence of SEQ ID NO;

128;

k) a VH sequence of SEQ ID NO;

131 and/or a VL sequence of SEQ ID NO;

130;

l) a VH sequence of SEQ ID NO;

133 and/or a VL sequence of SEQ ID NO;

132;

or

m) a VH sequence of SEQ ID NO;

135 and/or a VL sequence of SEQ ID NO;

134.

30. The antibody of claim 1, wherein the antibody is a monoclonal antibody.

31. The antibody of claim 1, wherein the antibody is a human, humanized, or chimeric antibody.

32. The antibody of claim 1, wherein the antibody is an antibody fragment that binds FcRH5.

33. The antibody of claim 1, wherein the antibody is an IgG1, IgG2a or IgG2b antibody.

34. The antibody of claim 1, wherein the antibody has one or more of the following characteristics:

a) cross reactive with full length human and cyno FcRH5, b) does not cross react with FcRH1, FcRH2, FcRH3, and/or FcRH4, c) binds to endogenous FcRH5, d) does not cross react with FcRH5a, and e) does not cross react with another Ig-like domain of FcRH5.

35. The antibody of claim 1, wherein the antibody is a bispecific antibody.

36. The antibody of claim 35, wherein bispecific antibody binds FcRH5 and CD3.

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

38. A host cell comprising the nucleic acid of claim 37.

39. A method of producing an antibody comprising culturing the host cell of claim 38 so that the antibody is produced.

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

41. The immunoconjugate of claim 40 having the formula Ab-(L-D)p, wherein:

(a) Ab is an isolated anti-FcRH5 antibody that binds an isoform c-specific region of the extracellular domain of FcRH5c;

(b) L is a linker;

(c) D is a drug selected from a maytansinoid, an auristatin, a calicheamicin, a pyrrolobenzodiazepine, and a nemorubicin derivative; and

(d) p ranges from 1-8.

42. The immunoconjugate of claim 41, wherein D is an auristatin.

43. The immunoconjugate of claim 42, wherein D has formula D_E

44. The immunoconjugate of claim 41, wherein the drug is MMAE.

45. The immunoconjugate of claim 41, wherein D is a pyrrolobenzodiazepine of Formula A:

46. The immunoconjugate of claim 45, wherein D has the structure:

47. The immunoconjugate of claim 45, wherein D has a structure selected from:

48. The immunoconjugate of claim 41, wherein D is a pyrrolobenzodiazepine of Formula B:

49. The immunoconjugate of claim 41, wherein D is a nemorubicin derivative.

50. The immunoconjugate of claim 49, wherein D has a structure selected from:

51. The immunoconjugate of claim 41, wherein the linker is cleavable by a protease.

52. The immunoconjugate of claim 51, wherein the linker comprises a val-cit dipeptide or a Phe-homoLys dipeptide.

53. The immunoconjugate of claim 41, wherein the linker is acid-labile.

54. The immunoconjugate of claim 53, wherein the linker comprises hydrazone.

55. The immunoconjugate of claim 53 having the formula:

56. The immunoconjugate of claim 46 having a formula selected from:

57. The immunoconjugate of claim 50 having a formula selected from:

58. The immunoconjugate of claim 41, wherein p ranges from 2-5.

59. A pharmaceutical formulation comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.

60. The pharmaceutical formulation of claim 59, further comprising an additional therapeutic agent.

61. A method of treating an individual having an FcRH5-positive cancer, the method comprising administering to the individual an effective amount of the antibody of claim 1.

62. The method of claim 61, wherein the FcRH5-positive cancer is a B-cell proliferative disorder.

63. The method of claim 61, further comprising administering an additional therapeutic agent to the individual.

64. A method of inhibiting proliferation of an FcRH5-positive cell, the method comprising exposing the cell to the antibody of claim 1 under conditions permissive for binding of the antibody and/or immunoconjugate to FcRH5 on the surface of the cell, thereby inhibiting proliferation of the cell.

65. The method of claim 64, wherein the cell is a B-cell.

66. The antibody of claim 1, wherein the antibody is conjugated to a label.

67. The antibody of claim 66, wherein the label is a positron emitter.

68. The antibody of claim 67, wherein the positron emitter is ⁸⁹Zr.

69. A method of detecting human FcRH5 in a biological sample comprising contacting the biological sample with the anti-FcRH5 antibody of claim 1 under conditions permissive for binding of the anti-FcRH5 antibody to a naturally occurring human FcRH5, and detecting whether a complex is formed between the anti-FcRH5 antibody and a naturally occurring human FcRH5 in the biological sample.

70. The method of claim 69, wherein the anti-FcRH5 antibody is an antibody comprising a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

52, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

76, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

100; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

4, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

16, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

28.

71. The method of claim 69, wherein the biological sample is a blood sample.

72. A method for detecting an FcRH5-positive cancer comprising (i) administering a labeled anti-FcRH5 antibody to a subject having or suspected of having a FcRH5-positive cancer, wherein the labeled anti-FcRH5 antibody comprises the anti-FcRH5 antibody of claim 1, and (ii) detecting the labeled anti-FcRH5 antibody in the subject, wherein detection of the labeled anti-FcRH5 antibody indicates a FcRH5-positive cancer in the subject.

75. The method of claim 69, wherein the anti-FcRH5 antibody is an antibody comprising a) a heavy chain comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO:

55, HVR-H2 comprising the amino acid sequence of SEQ ID NO;

79, and HVR-H3 comprising the amino acid sequence of SEQ ID NO;

103; and

/or b) a light chain comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO;

7, HVR-L2 comprising the amino acid sequence of SEQ ID NO;

19, and HVR-L3 comprising the amino acid sequence of SEQ ID NO;

31.

76. A pharmaceutical formulation comprising the immunoconjugate of claim 41 and a pharmaceutically acceptable carrier.

77. A method of treating an individual having an FcRH5-positive cancer, the method comprising administering to the individual an effective amount of the immunoconjugate of claim 41.

78. A method of inhibiting proliferation of an FcRH5-positive cell, the method comprising exposing the cell to the immunoconjugate of claim 41 under conditions permissive for binding of the antibody and/or immunoconjugate to FcRH5 on the surface of the cell, thereby inhibiting proliferation of the cell.

73. The method of 72, wherein the labeled anti-FcRH5 antibody comprises an anti-FcRH5 antibody conjugated to a positron emitter.

74. The method of claim 73, wherein the positron emitter is ⁸⁹Zr.